Regioselective Ru(II)/Pd(0) Dual Catalysis: One-Pot C-H Diarylation of Five-Membered Heterocyclic Derivatives

Article abstract of DOI:10.1021/acs.joc.0c01983

Herein, we report a one-pot site-selective dual metal catalyzed C-H diarylation reaction for the synthesis of multiarylated thiophene and furan derivatives in yields up to 92%. The regioselectivity of the developed methodology was achieved with the sequential use of two metal catalysts within a single vessel, starting with a Ru(II)-catalyzed C3 arylation assisted by an azine directing group, followed by a Pd(0)-catalyzed C-H functionalization on the C5-position of the five-membered heterocycle. Furthermore, the kinetic studies support that the position of the nitrogen atom within the azine moiety exhibits an evident effect on the efficiency of the ruthenium-catalyzed arylation step.

Full text of DOI:10.1021/acs.joc.0c01983

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Regioselective Ru(II)/Pd(0) Dual Catalysis: One-Pot C−H Diarylation
of Five-Membered Heterocyclic Derivatives
̌
̌
̌
Hamad H. Al Mamari, Uros Groselj, Franc Pozgan, and Helena Brodnik*
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ABSTRACT: Herein, we report a one-pot site-selective dual metal
catalyzed C−H diarylation reaction for the synthesis of multi-
arylated thiophene and furan derivatives in yields up to 92%. The
regioselectivity of the developed methodology was achieved with
the sequential use of two metal catalysts within a single vessel,
starting with a Ru(II)-catalyzed C3 arylation assisted by an azine
directing group, followed by a Pd(0)-catalyzed C−H functionaliza-
tion on the C5-position of the five-membered heterocycle. Furthermore, the kinetic studies support that the position of the nitrogen
atom within the azine moiety exhibits an evident effect on the efficiency of the ruthenium-catalyzed arylation step.
and regioselectivity, affording a wide diversity of interesting
azacyclic scaffolds.19 A report on direct arylation of imidazo-
[1,5-a]azines through ruthenium and palladium catalysis in the
same flask was published by Charette and co-workers, where
the protocol included a two-step sequential C−H arylation
reaction allowing rapid synthesis of highly conjugated
compounds.20 In 2016, Sutherland and co-workers developed
a procedure for the formation of diversely functionalized
aminobicyclo[4.3.0]nonanes as a one-pot three-step tandem
process that involved a palladium-catalyzed Overman
rearrangement with a ruthenium-catalyzed ring closing enyne
metathesis and hydrogen bond directed Diels−Alder reac-
tion.21 In 2016, Lautens and co-workers reported a dual-metal-
catalyzed enantioselective one-pot synthesis that combines a
ruthenium-catalyzed C−H functionalization and a palladium-
catalyzed asymmetric allylic alkylation reaction for the
formation of chiral 3-allyl-3-aryl oxindoles.22 A highly
interesting multicomponent tandem reaction was developed
by Prestat and co-workers, as they performed a one-pot Pd/
Pd/Ru/Pd-catalyzed procedure allowing the formation of four
C−C bonds through four consecutive catalytic cycles.23
INTRODUCTION
■
The development of synthetic methods to perform a successful
multiple bond formation within a single vessel without the
isolation or purification of intermediates continues to be a goal
for synthetic chemists.1−9 The importance of such step-
economical processes also lies in the reduction of cost, waste,
and time, which are the essential aspects of green and
sustainable chemistry.10 The immense progress of transition
metal (TM) catalysis over the last five decades has allowed the
development of efficient novel one-pot transformations in
which all newly formed bonds are based on TM catalysis.11 In
order to access a large number of reactions within a single
vessel, one-pot processes catalyzed by only one transition-
metal complex often limits access to chemical space diversity.
Therefore, the rise of dual catalysis,12−15 where two different
catalysts activate a specific site in the molecule, makes
multitransformation reactions highly regioselective.
Focused on one-pot C−H functionalization reactions based
on ruthenium and palladium catalysis, an early report by Trost
and Machacek describes a one-pot procedure for the formation
of diastereoselective heterocycles combining a Pd-catalyzed
asymmetric allylic alkylation with a Ru-catalyzed ene-yne
coupling.16 Soon after, in 2005, Chang and co-workers
reported a novel application of cooperative catalysis to the
coupling of an aldehyde with iodoarenes or organostannanes,
in which Ru and Pd collaborate, presumably through catalytic
transmetalation pathways for the preparation of ketones from
aldehydes.17 An important contribution was also made by
Ackermann and Althammer as they reported a one-pot
synthesis of 2-aryl- and 2-vinylindoles, which relies on a
regioselective Ru3(CO)12-catalyzed hydroamination followed
by a palladium-catalyzed intramolecular Heck reaction.18
Anderson and co-workers described the first example of
palladium-catalyzed enynamide cycloisomerization, together
with a ruthenium-catalyzed process resulting in high stereo-
Recently, we have reported a paper that focuses on the
reactivity of C2-quinoline-substituted five-membered hetero-
cycles in a Pd-catalyzed direct C−H functionalization reaction
(Scheme 1a).24 Unfortunately, the presence of only one TM
catalyst rendered the protocol to be nonregioselective, as direct
arylation proceeded on both the C3 (nitrogen-directed
Received: August 17, 2020
Published: January 29, 2021
https://dx.doi.org/10.1021/acs.joc.0c01983
© 2021 American Chemical Society
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Scheme 1. Transition-Metal Catalyzed C−H Arylation of
Five-Membered Heterocycles
Table 1. Optimization of the Ru-Catalyzed Direct C−H
a
Arylation of 2-(Thiophene-2-yl)quinoline (1a) with 4a
e
entry
base
solvent
conversion (%)
b
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
NaOAc
KOAc
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
NMP
THF
MeCN
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
10
71
63
100
100
100
80
c
2
d
3
4
5
6
7
8
9
10
11
12
reaction) and the C5 (reaction at more reactive position)
position of the five-membered heterocycle; however, the
synthesized compounds25 were exemplified as promising
inhibitors toward human cysteine protease Cathepsin B in
tumor progression.26 Driven to develop a methodology that
would allow highly regioselective C−H arylation of five-
membered heterocyclic derivatives, we turned our attention to
the combination of palladium and ruthenium catalysis, as the
latter functions solely through the directing group coordina-
tion. Herein, we report a two-step sequential one-pot direct
C−H arylation catalyzed by ruthenium and palladium for the
rapid synthesis of highly conjugated heteroaromatic com-
pounds (Scheme 1b).
11
100
100
31
26
a
Standard reaction conditions: 1a (0.5 mmol), 4a (0.5 mmol), [Ru(p-
cymene)Cl2]2 (10 mol %), PPh3 (20 mol %), KOPiv (40 mol %), base
b
(2 equiv), solvent (2 mL), 140 °C, 24 h, argon. Reaction carried out
c
without PPh3 and KOPiv. Reaction carried out without PPh3.
d
e
Reaction carried out without KOPiv. Conversion determined on the
1
basis of H NMR analysis of the crude reaction mixture.
RESULTS AND DISCUSSION
■
On the basis of our previous study,24 we chose 2-(thiophene-2-
yl)quinoline (1a) as the model substrate for the optimization
of the Ru-catalyzed C−H functionalization step. We
anticipated that the reaction would proceed exclusively on
the C3 position of the thiophene ring through the formation of
a more stable five-membered ruthenacycle, whereas using
palladium already in the first C−H functionalization step
would afford C3 as well as C5 arylated products, as reported by
us24 and Doucet and co-workers.27,28 We initiated our
investigation with the reaction of 1a with 4-bromoacetophe-
none (4a) in the presence of [Ru(p-cymene)Cl2]2 as the
selected (pre)catalyst. The reactions were run at 140 °C for 24
h. The use of solely [Ru(p-cymene)Cl2]2 (10 mol %) gave only
a 10% conversion to the desired product 5aa (Table 1, entry
1), whereas the combination of PPh3 and KOPiv allowed the
exclusive formation of the monoarylated product 5aa in
quantitative yield (Table 1, entry 4). The use of either PPh3 or
KOPiv as a sole ligand gave lower conversion (Table 1, entries
2 and 3). KOPiv as a carboxylate ligand is presumed to
coordinate to the metal center and facilitate the C−H bond
cleavage to significantly enhance the direct functionalization
process.29 The combination of both, a phosphine and
carboxylate ligand, also proved beneficial in our previous
report on the Ru-catalyzed C−H bond functionalization of
quinazolines.30−32 Next, we turned our attention to solvent
screening. Among the tested solvents, 1,4-dioxane, toluene,
and NMP (N-methyl-2-pyrrolidone) all proved to be efficient
(Table 1, entries 4−6). However, 1,4-dioxane was chosen as
the leading solvent, as toluene and NMP did not perform well
in the second, Pd-catalyzed arylation step. Furthermore, the
screening of different bases showed full conversion to the
desired product 5aa in the presence of K2CO3, Na2CO3, and
K3PO4 (Table 1, entries 4, 9, and 10), whereas acetate bases
performed poorly (Table 1, entries 11 and 12). Additionally, a
series of phosphine and nitrogen-based ligands as well as
carboxylate ligands were also examined (for results, see the
Supporting Information), but the combination of PPh3 and
KOPiv surpassed them all (Table 1, entry 4). Finally, lowering
the reaction temperature resulted in an incomplete conversion
to 5aa after 24 h (for results, see the Supporting Information).
With the optimized reaction conditions ([Ru(p-cymene)-
Cl2]2 (10 mol %), PPh3 (20 mol %), KOPiv (40 mol %),
K2CO3 (2 equiv), 1,4-dioxane, 140 °C, 24 h) in hand, we
explored the versatility of quinoline-assisted direct C−H
arylation on the C3 position of the thiophene ring (Scheme
2). A series of para-substituted aryl bromides were tested,
showing high tolerance toward electronic effects of the
coupling partner and affording products in moderate to
excellent yields (5aa−f, 50−95%). Since the Ru-catalyzed
direct arylation step is exclusively controlled by a present
directing group, we were curious to see if the position of the
nitrogen atom in the site directing the azine moiety affects the
reactivity of the in situ formed Ru species. Satisfyingly, both
azine derivatives, 3-(thiophen-2-yl)isoquinoline (2a) and 2-
(thiophen-2-yl)quinazoline (3a), produced noticeably higher
conversions compared to our model substrate 1a, yielding the
final products in good to excellent yields (6aa−f, 71−99%;
7aa−f, 85−98%). Moreover, ortho- and meta-substituted aryl
bromides were also exemplified as suitable coupling partners
(6ag−i, 80−92%; 7ag, 85%; 7ah, 81%), proving the method’s
versatile aspect. Comparing the quinoline, isoquinoline, and
quinazoline moieties, we assume that the difference of the
efficiency of the Ru-catalyzed arylation may originate in the
formation of a stable ruthenacycle complex. Thus, we managed
to isolate and determine the structure of Ru-quinazoline-
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a
Scheme 2. Scope of Ru-Catalyzed Direct C3 Arylation of Compounds 1−3 with Aryl Bromides 4
a
The yields given refer to the isolated pure products 5−7.
complex A using X-ray analysis (Scheme 2), which proved that
the metal center favors coordination to the N3-nitrogen rather
than to the N1-nitrogen atom of quinazoline; a similar finding
also made by Gandhi and co-workers.33 Furthermore, we also
determined that the reaction in the case of quinazoline 3a
proceeded to complete conversion to 7aa at 120 °C after 24 h,
whereas in the case of isoquinoline 2a to 6aa, it occurred at an
even lower temperature, 100 °C.
To assess the broadness of the method even further, we
managed to prepare a set of arylated furan derivatives (Scheme
2), which were more challenging compared to their thiophene
analogues. To achieve satisfying conversions, the reaction time
needed to be prolonged to 48 h. Therefore, reacting 1b with 4a
yielded C3-arylated product 5ba in a good 68% isolated yield.
Pleasingly, the Ru-catalyzed arylation of furan derivatives 2b
and 3b with 4 also showed high reactivity and good substituent
tolerance with various aryl bromides, as electron-donating and
electron-withdrawing groups showed no influence on the yield
of the formed products; C3-arylated furans were isolated in
moderate to good yields (6ba−e, 29−80%; 7ba−f, 77−88%).
To gain a better understanding in the difference of the
reactivity of the studied azine derivatives, a set of control
experiments were conducted. First, we were interested in the
kinetics of the Ru-catalyzed arylation (Figure 1). The progress
of the reaction of quinoline 1a, isoquinoline 2a, and
quinazoline 3a with 4a, respectively, under the standard
reaction conditions was followed over the period of 6 h. The
crude reaction mixture was analyzed by 1H NMR to determine
the conversion of the starting material to the monoarylated
product. The data show (Figure 1) superior reactivity of the
isoquinoline substrate 2a.
To support our assumption on this matter, three separate
competition experiments were carried out. A 1:1 mixture of
two substrates (1a and 2a; 2a and 3a; 2b and 3b) was reacted
with an overall 1 equiv of 4-bromoacetophenone (4a) under
the standard reaction conditions (Scheme 3). The results of
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the competition experiments are in line with the observed
difference in the initial reactivity (Figure 1) of the three
nitrogen-based substrates 1−3, revealing the isoquinoline
derivative 2a to be the most reactive, followed by the
quinazoline 3a and the quinoline 1a as the least reactive
substrate. The observed results suggest that the position of the
nitrogen atom in the azine moiety does have a noticeable effect
on the efficiency of the Ru-catalyzed reaction. Therefore, one
can conclude that, in the Ru-catalyzed arylation step, the
isoquinoline moiety exhibits the strongest directing potential
for the C3 arylation of the five-membered heterocycle.
After completion of the Ru-catalyzed functionalization step,
we continued our investigation on the second, Pd-catalyzed
arylation. The reaction would proceed on the C5 position of
the five-membered heterocycle, which represents the more
reactive position in the ring opposed to C4.34 For optimization
of the Pd-catalyzed arylation, compound 5aa was chosen as the
model substrate and 4-bromobenzonitrile (4c), as the selected
aryl bromide. A set of different palladium catalysts (Table 2)
Figure 1. Progress of the reaction over time of Ru-catalyzed C−H
arylation of substrates 1a/2a/3a under standard reaction conditions.
Conversion determined on the basis of 1H NMR analysis of the crude
reaction mixture.
Table 2. Optimization of the Pd-Catalyzed Direct C−H
Arylation of Compound 5aa with 4-Bromobenzonitrile
a
(4c)
a
Scheme 3. Competition Experiments
c
entry
Pd-cat.
conversion (%)
1
PdCl(C3H5)(dppe)
PdCl(C3H5)(dppb)
Pd(OAc)2
Pd(PPh3)4
Pd(dba)4
80
66
62
56
6
2
3
b
4
5
a
Standard reaction conditions: 5aa (0.5 mmol), 4c (1.0 mmol), Pd-
cat. (10 mol %), K2CO3 (3 equiv), 1,4-dioxane (2 mL), 130 °C, 48 h,
b
argon. PPh3 (20 mol %) was added to the reaction mixture.
c
1
Conversion determined on the basis of H NMR analysis of the
crude reaction mixture.
were tested, out of which PdCl(C3H5)(dppe), prepared
according to Jutand and co-workers,35 gave the best result
(Table 2, entry 1). It should be noted that in the case of
isoquinoline 6aa the combination of Pd(OAc)2 (10 mol %)
with PPh3 (20 mol %) resulted in a 95% conversion to the final
product 9aa, whereas PdCl(C3H5)(dppe) gave a 66%
conversion. For achieving high conversions to the desired
diarylated products 8−10, the reactions were run for 48 h at
130 °C.
Finally, we wanted to combine both metal-catalyzed
arylation steps in a single flask to explore the possibility of
developing a sequential one-pot procedure (Scheme 4). The
initial azine derivatives 1−3, in the presence of [Ru(p-
cymene)Cl2]2 (10 mol %), PPh3 (20 or 40 mol %), KOPiv
(40 mol %), and K2CO3 (5 equiv) in 1,4-dioxane, were reacted
with 1 equiv of aryl bromide 4 at 140 °C for 24 h. After
completion of the Ru-catalyzed arylation step, PdCl(C3H5)-
(dppe) (10 mol %) or Pd(OAc)2 (10 mol %) and the
corresponding aryl bromide 4 (2 equiv) were added to the
reaction flask, and the mixture was stirred for an additional 48
h at 130 °C. Pleasingly, the transformations carried out as a
a
Competition experiments between quinoline derivative 1a and
isoquinoline derivative 2a (top); isoquinoline derivative 2a and
quinazoline derivative 3a (bottom); isoquinoline derivative 2b and
quinazoline derivative 3b (bottom). The ratio between the
monoarylated products was determined on the basis of 1H NMR
analysis of the crude reaction mixture.
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Scheme 4. Scope of One-Pot Sequential Ru/Pd-Catalyzed Regioselective Direct Arylation of Five-Membered Heterocycles 1−
a
3
a
The yields given refer to the isolated pure products 8−10 obtained in the one-pot procedure. The yields in brackets were obtained in the Pd-
catalyzed arylation step starting from isolated intermediate 5−7. In the case of quinolines 5 and quinazolines 7, PdCl(C3H5)(dppe) was chosen as
the catalyst, whereas Pd(OAc)2 was chosen in the case of isoquinoline 6; therefore, 40 mol % of PPh3 was added in the first C−H arylation step.
one-pot reaction proceeded equally well in comparison to
arylations performed stepwise (with purification of intermedi-
ates 5−7). Even the use of ortho- and meta-substituted aryl
bromides yielded the final diarylated products in good yields
with the exception of 10ae (29%). Moreover, products 9ba
(92%) and 9bb (75%) were isolated in significantly higher
yields in the one-pot synthesis, proving the efficiency,
simplicity, and economical aspect of the developed method-
ology for the formation of highly conjugated heterocyclic
systems. Additionally, an X-ray analysis of two final diarylated
products 8ba and 9ab undoubtedly confirmed the established
arylation sequence of the developed protocol (Scheme 4).
The developed dual metal one-pot diarylation sequence was
also tested on a gram scale where 1.50 g of the starting
quinazoline derivative 3a was reacted with 1 equiv of 4-
bromoacetophenone (4a) under Ru-catalyzed reaction con-
ditions (Scheme 5). After completion of the first C3 arylation
step, 2 equiv of 4b along with 10 mol % of PdCl(C3H5)(dppe)
were added to the reaction mixture for the second arylation to
proceed on the C5-position of the thiophene ring. Hence, the
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Scheme 5. Scale-up Synthesis of 10ac
150 K. The data was processed using CrysAlis PRO.36 Using
Olex2.1.2.,37 the structures were solved by direct methods
implemented in SHELXS38 or SHELXT39 and refined by a full-
matrix least-squares procedure based on F2 with SHELXT-2014/7.40
All nonhydrogen atoms were refined anisotropically. Hydrogen atoms
were placed in geometrically calculated positions and were refined
using a riding model. The drawings and the analysis of bond lengths,
angles, and intermolecular interactions were carried out using
Mercury41 and Platon.42
Synthesis of Quinoline Derivatives 1 and Isoquinoline
Derivatives 2.25 2-Bromoquinoline or 3-bromoisoquinoline (5.00
mmol, 1.04 g), 2-thienylboronic acid or 2-furanylboronic acid (7.50
mmol), Pd(OAc)2 (56 mg, 0.25 mmol), PPh3 (131 mg, 0.50 mmol),
and K2CO3 (1.38 g, 10 mmol) were dissolved in a mixture of 1,4-
dioxane (12 mL) and water (3 mL). The reaction mixture was stirred
in a sealed glass tube at 100 °C for 24 h under an inert atmosphere.
The mixture was allowed to cool to room temperature; water was
added (10 mL), and the product was extracted into EtOAc (3 × 10
mL). The combined organic layers were dried (Na2SO4) and filtered,
and the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography.
final diarylated product 10ac was isolated in a good 80%
overall yield.
CONCLUSIONS
■
In conclusion, we have developed a regioselective dual metal
Ru(II)/Pd(0) catalyzed one-pot C−H diarylation reaction of
five-membered heterocycles allowing access to a variety of
polyconjugated molecular architectures. The methodology
demonstrates its simplicity and regioselectivity by implement-
ing two consecutive arylation steps within a single flask with
the use of a nitrogen-based directing group to carry out the Ru-
catalyzed reaction at the C3 site, followed by a Pd-catalyzed C5
arylation. Furthermore, competition studies between the azine
and diazine derivatives in the Ru-catalyzed arylation step
indicate that, among the quinoline, quinazoline, and isoquino-
line moieties, the latter possesses the strongest directing
efficiency for the direct C3 arylation of the five-membered
heterocyclic derivatives, even overpowering the quinazoline
structural motif (bearing two nitrogen atoms; both capable of
directing the site of arylation).
2-(Thiophen-2-yl)quinoline (1a). Column chromatography on
silica gel (eluting with petroleum ether/EtOAc, 50/1). White solid
(1.00 g, 95%). Melting point = 129−131 °C. FT-IR (ATR, neat):
3100, 3059, 1614, 1551, 1498, 1359, 1142, 1056, 933, 786, 708 cm−1.
1H NMR (500 MHz, CDCl3): δ 8.13 (d, J = 8.6 Hz, 1 H), 8.08 (d, J =
EXPERIMENTAL SECTION
■
General Information. The reagents and solvents were used as
received from commercial suppliers. A heating mantle was used as the
heat source for all the described transformations. Reactions were
monitored by analytical thin-layer chromatography (TLC), and
visualization of the developed TLC chromatogram was performed
by UV absorbance. Column chromatography was performed on 230−
400 mesh silica gel with the indicated solvent system. Merck silica gel
60 PF254 containing gypsum was used to prepare chromatotron
plates. Radial chromatography was performed with a Harrison
Research model 7924 T chromatotron. Yields refer to chromato-
graphically and spectroscopically (1H and 13C NMR) homogeneous
materials. Melting points are uncorrected. Infrared spectra were
recorded on a FT-IR spectrometer and are reported in reciprocal
centimeters (cm−1). Routine nuclear magnetic resonance spectra were
recorded on a Bruker Avance 500 MHz spectrometer in CDCl3.
Chemical shifts for 1H NMR spectra are recorded in parts per million
(ppm) from tetramethylsilane as an internal standard. The multi-
plicities are reported as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), dd (doublet of doublets), and ddd (doublet
doublet of doublets), number of equivalent nuclei (by integration),
and coupling constants (J) quoted in Hertz (Hz). Chemical shifts for
the 13C NMR spectra are recorded in parts per million from
tetramethylsilane using the central peak of the solvent resonance as an
internal standard (CDCl3 triplet at δ = 77.160 ppm). All spectra were
obtained with complete proton decoupling. High-resolution mass
spectra were recorded on an Agilent 6224 Accurate Mass TOF/MS
instrument by electrospray ionization. Single-crystal X-ray diffraction
data was collected on the Agilent Technologies SuperNova Dual
diffractometer with an Atlas detector using monochromated Mo Kα
radiation (λ = 0.71073 Å) and Cu Kα radiation (λ = 1.54184 Å) at
8.5 Hz, 1 H), 7.80−7.76 (m, 2 H), 7.73 (dd, J = 3.7, 1.1 Hz, 1 H),
7.69 (ddd, J = 8.5, 6.9, 1.5 Hz, 1 H), 7.50−7.46 (m, 2 H), 7.16 (dd, J
= 5.1, 3.6 Hz, 1 H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.3,
148.1, 145.4, 136.6, 129.8, 129.3, 128.5, 128.0, 127.5, 127.2, 126.1,
125.8, 117.6 ppm. HRMS (ESI+): m/z calcd. for C13H10NS (M +
H)+, 212.0528; found, 212.0522.
2-(Furan-2-yl)quinoline (1b). Column chromatography on silica
gel (eluting with petroleum ether/EtOAc, 50/1). White solid (737
mg, 76%). Melting point = 87−89 °C. FT-IR (ATR, neat): 3106,
1
3061, 1385, 1306, 1286, 1126, 1008, 912, 787, 741 cm−1. H NMR
(500 MHz, CDCl3): δ 8.17 (dd, J = 8.6, 0.8 Hz, 1 H), 8.13 (dd, J =
8.5, 1.0 Hz, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.79 (dd, J = 8.0, 1.4 Hz,
1 H), 7.71 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.63 (dd, J = 1.8, 0.8 Hz, 1
H), 7.50 (ddd, J = 8.0, 6.8, 1.1 Hz, 1 H), 7.22 (dd, J = 3.4, 0.8 Hz, 1
H), 6.60 (dd, J = 3.4, 1,8 Hz, 1 H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 153.7, 149.0, 148.1, 144.1, 136.6, 129.8, 129.4, 127.5,
127.1, 126.2, 117.4, 112.2, 110.1 ppm. HRMS (ESI+): m/z calcd. for
C13H10NO (M + H)+, 196.0757; found, 196.0751.
3-(Thiophen-2-yl)isoquinoline (2a). Column chromatography on
silica gel (eluting with petroleum ether/EtOAc, 10/1). Yellow solid
(1.02 g, 97%). Melting point = 114−119 °C. FT-IR (ATR, neat):
1
3051, 2162, 1959, 1622, 1488, 1345, 1013, 939, 856, 699 cm−1. H
NMR (500 MHz, CDCl3): δ 9.22 (s, 1H), 7.98 (s, 1H), 7.95 (dd, J =
8.2, 1.0 Hz, 1H), 7.82 (dd, J = 8.3, 1.0 Hz, 1H), 7.70 (dd, J = 3.7, 1.2
Hz, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.55 (ddd, J = 8.1, 6.9,
1.1 Hz, 1H), 7.40 (dd, J = 5.0, 1.1 Hz, 1H), 7.15 (dd, J = 5.0, 3.7 Hz,
1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.6 (2C), 146.7,
145.2, 136.6, 130.9, 128.3, 127.9, 127.9, 127.0, 126.8, 124.0, 114.5
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https://dx.doi.org/10.1021/acs.joc.0c01983
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Article
ppm. HRMS (ESI+): m/z calcd. for C13H10NS (M + H)+, 212.0528;
found, 212.0534.
EtOAc, 20/1). Yellow solid (161 mg, 91%). Melting point = 112−115
°C. FT-IR (ATR, neat): 3041, 1614, 1552, 1320, 1161, 1102, 947,
852, 783, 727 cm−1. 1H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 8.4,
0.9 Hz, 1H), 7.91 (d, J = 8.6, 0.8 Hz, 1H), 7.76−7.70 (m, 2H), 7.62
(d, 2H), 7.56−7.48 (m, 4H), 7.17 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 8.6
Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.9, 148.4,
140.8, 140.5 (C−F, 1JC−F = 3.9 Hz), 139.0, 136.2, 130.8, 130.0, 129.7,
3-(Furan-2-yl)isoquinoline (2b). Column chromatography on silica
gel (eluting with petroleum ether/EtOAc, 10/1). Yellow solid (890
mg, 91%). Melting point = 71−75 °C. FT-IR (ATR, neat): 3113,
1
2982, 1725, 1620, 1484, 1317, 1155, 998, 864, 738 cm−1. H NMR
(500 MHz, CDCl3): δ 9.23 (s, 1H), 8.02 (s, 1H), 7.94 (dd, J = 8.2,
1.0 Hz, 1H), 7.84 (dd, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.2, 6.8, 1.2
Hz, 1H), 7.57−7.53 (m, 2H), 7.13 (dd, J = 3.3, 0.8 Hz, 1H), 6.57 (dd,
J = 3.4, 1.8 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
154.3, 152.7, 143.6, 143.1, 136.5, 130.9, 127.9, 127.9, 127.1, 127.0,
114.3, 112.3, 108.4 ppm. HRMS (ESI+): m/z calcd. for C13H10NO
(M + H)+, 196.0757; found, 196.0754.
3
129.7, (C−F, JC−F = 32.5 Hz), 129.5, 127.8, 127.6, 127.1, 126.8,
2
1
125.7 (C−F, JC−F = 3.9 Hz), 124.4 (C−F, JC−F = 272.5 Hz), 120.9
ppm. 19F NMR (471 MHz, CDCl3): δ −62.5 ppm. HRMS (ESI+): m/
z calcd for C20H13F3NS (M + H)+, 356.0715; found, 356.0713.
4-(2-(Quinolin-2-yl)thiophen-3-yl)benzonitrile (5ac). Radial chro-
matography on silica gel (eluting with petroleum ether/EtOAc, 50/1).
Yellow solid (78 mg, 50%). Melting point = 137−139 °C. FT-IR
(ATR, neat): 3056, 2223, 1906, 1590, 1311, 1223, 992, 840, 822, 741
cm−1. 1H NMR (500 MHz, CDCl3): δ 8.07 (dd, J = 8.5, 0.9 Hz, 1H),
7.93 (dd, J = 8.6, 0.9 Hz, 1H), 7.76 (dd, J = 8.1, 1.4 Hz, 1H), 7.74−
7.70 (m, 1H), 7.64 (AA′BB′, J = 8.56 Hz, 2H), 7.56−7.47 (m, 4H),
7.16 (d, J = 5.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H) ppm. 13C{1H}
NMR (126 MHz, CDCl3): δ 152.5, 148.4, 141.6, 141.1, 138.5, 136.3,
132.5, 130.5, 130.1 (2C), 129.5, 128.0, 127.6, 127.1, 126.9, 121.0,
118.9, 111.3 ppm. HRMS (ESI+): m/z calcd for C20H13N2S (M +
H)+, 313.0794; found, 313.0794.
Synthesis of Quinazoline Derivatives 3.43 A solution of 2-
aminobenzylamine (10 mmol, 1.22 g) and thiophene-2-carbaldehyde
or 2-furaldehyde (10 mmol) in MeOH (35 mL) was stirred at room
temperature for 20 h. The mixture was then cooled to 0 °C to which
10% NaOCl (55 mmol, 34 mL) was added dropwise over a period of
30 min and further stirred at room temperature for 5 h. The mixture
was then washed with brine (40 mL) and extracted with EtOAc (2 ×
50 mL). The combined organic layers were dried (Na2SO4) and
filtered, and the solvent was evaporated under reduced pressure. The
crude product was purified by column chromatography.
2-(3-(p-Tolyl)thiophen-2-yl)quinoline (5ad). Radial chromatogra-
phy on silica gel (eluting with petroleum ether/EtOAc, 5/1). White
solid (99 mg, 66%). Melting point = 123−125 °C. FT-IR (ATR,
neat): 3100, 3076, 1592, 1497, 1422, 1228, 1075, 858, 816, 752 cm−1.
1H NMR (500 MHz, CDCl3): δ 8.12 (dd, J = 8.3, 0.9 Hz, 1H), 7.85
(dd, J = 8.7, 0.8 Hz, 1H), 7.76−7.65 (m, 2H), 7.52−7.43 (m, 2H),
7.29 (AA′BB′, J = 8.06 Hz, 2H), 7.20−7.12 (m, 4H), 2.40 (s, 3H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 153.6, 148.3, 140.9,
139.4, 137.6, 135.8, 133.9, 131.3, 129.7, 129.5, 129.4, 129.3, 127.5,
127.4, 127.0, 126.4, 121.0, 21.4 ppm. HRMS (ESI+): m/z calcd for
C20H16NS (M + H)+, 302.0998; found, 302.0997.
2-(3-(4-Methoxyphenyl)thiophen-2-yl)quinoline (5ae). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
50/1). White solid (103 mg, 65%). Melting point = 125−127 °C. FT-
IR (ATR, neat): 2999, 2842, 1573, 1458, 1302, 1123, 994, 828, 725,
688 cm−1. 1H NMR (500 MHz, CDCl3): δ 8.11 (dd, J = 8.5, 0.9 Hz,
1H), 7.86 (dd, J = 8.7, 0.8 Hz, 1H), 7.75−7.66 (m, 2H), 7.54−7.43
(m, 2H), 7.32 (AA′BB′, J = 8.75 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H),
7.13 (d, J = 5.1 Hz, 1H), 6.90 (AA′BB′, J = 8.81 Hz, 2H), 3.84 (s,
3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 159.3, 153.7, 148.3,
140.6, 139.0, 135.7, 131.2, 130.6, 129.7, 129.4, 129.2, 127.5, 127.4,
127.0, 126.4, 121.0, 114.2, 55.4 ppm. HRMS (ESI+): m/z calcd for
C20H16NOS (M + H)+, 318.0947; found, 318.0946.
2-(Thiophen-2-yl)quinazoline (3a). Column chromatography on
silica gel (eluting with petroleum ether/EtOAc, 10/1). Light yellow
solid (1.98 g, 93%). Melting point = 136−139 °C. FT-IR (ATR,
neat): 3109, 3080, 3061, 1616, 1583, 1552, 1423, 1395, 1377, 1044,
800, 763, 708 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.36 (d, J = 0.8
Hz, 1H), 8.15 (dd, J = 3.7, 1.2 Hz, 1H), 8.03−7.99 (m, 1H), 7.90−
7.85 (m, 2H), 7.57 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.52 (dd, J = 5.0,
1.2 Hz, 1H), 7.20 (dd, J = 5.0, 3.7 Hz, 1H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 160.7, 158.0, 150.8, 144.0, 134.5, 130.1, 129.4,
128.5, 128.3, 127.4, 127.1, 123.5 ppm. HRMS (ESI+): m/z calcd. for
C12H9N2S (M + H)+, 213.0481; found, 213.0484.
2-(Furan-2-yl)quinazoline (3b). Column chromatography on silica
gel (eluting with petroleum ether/EtOAc, 10/1). Light yellow solid
(1.53 g, 78%). Melting point = 118−121 °C. FT-IR (ATR, neat):
3132, 3099, 3055, 1587, 1480, 1413, 1379, 1166, 1074, 1002, 765,
721 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.37 (d, J = 0.8 Hz, 1H),
8.11−8.06 (m, 1H), 7.92−7.85 (m, 2H), 7.68 (dd, J = 1.8, 0.9 Hz,
1H), 7.61−7.56 (m, 1H), 7.45 (dd, J = 3.4, 0.9 Hz, 1H), 6.61 (dd, J =
3.4, 1.7 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 160.9,
154.2, 152.6, 150.5, 145.5, 134.7, 128.5, 127.4, 127.4, 123.5, 114.2,
112.5 ppm. HRMS (ESI+): m/z calcd. for C12H9N2O (M + H)+,
197.0709; found, 197.0712.
General Method for Ruthenium-Catalyzed C−H Arylation. A
mixture of the azine substrates 1−3 (0.50 mmol), aryl bromide 4
(0.50 mmol), [Ru(p-cymene)Cl2]2 (0.05 mmol, 31 mg), PPh3 (0.10
mmol, 26 mg), KOPiv (0.20 mmol, 28 mg), and K2CO3 (1.00 mmol,
138 mg) in 1,4-dioxane (2 mL) was stirred for 24 h at 140 °C under
argon in a sealed tube. The mixture was then cooled to room
temperature, and DCM (10 mL) was added, after which the inorganic
salts were filtered off and washed with DCM (5 mL). The filtrate was
concentrated under reduced pressure, and the residue was purified by
radial chromatography on silica gel to yield the monoarylated
products 5−7.
1-(4-(2-(Quinolin-2-yl)thiophen-3-yl)phenyl)ethan-1-one (5aa).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 10/1). Greenish-brown solid (156 mg, 95%). Melting point =
100−103 °C. FT-IR (ATR, neat): 3034, 1672, 1614, 1500, 1261,
1014, 823, 767, 721, 655 cm−1. 1H NMR (500 MHz, CDCl3): δ 8.10
(d, J = 8.4, 1.0 Hz, 1H), 7.95 (AA′BB′, J = 8.55 Hz, 2H), 7.88 (d, J =
8.7, 0.8 Hz, 1H), 7.77−7.68 (m, 2H), 7.55−7.46 (m, 4H), 7.18 (d, J =
5.2 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 2.63 (s, 3H) ppm. 13C{1H}
NMR (126 MHz, CDCl3): δ 197.9, 152.9, 148.4, 141.7, 140.8, 139.4,
136.2, 136.1, 130.8, 130.0, 129.6, 129.5, 128.8, 127.8, 127.6, 127.1,
126.7, 121.1, 26.8 ppm. HRMS (ESI+): m/z calcd for C21H16NOS (M
+ H)+, 330.0947; found, 330.0942.
N,N-Dimethyl-4-(2-(quinolin-2-yl)thiophen-3-yl)aniline (5af). Ra-
dial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 50/1). Yellow solid (96 mg, 58%). Melting point = 158−160
°C. FT-IR (ATR, neat): 3104, 2883, 2802, 1542, 1500, 1343, 1194,
1
1067, 816, 741 cm−1. H NMR (500 MHz, CDCl3): δ 8.12 (dd, J =
8.5, 0.9 Hz, 1H), 7.86 (dd, J = 8.7, 0.8 Hz, 1H), 7.76−7.64 (m, 2H),
7.51−7.46 (m, 1H), 7.45 (d, J = 5.1 Hz, 1H), 7.30−7.26 (m, 3H),
7.14 (d, J = 5.2 Hz, 1H), 6.72 (AA′BB′, J = 8.89 Hz, 2H), 3.00 (s,
6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 154.1, 150.0, 148.3,
141.3, 138.0, 135.5, 131.3, 130.2, 129.6, 129.4, 127.5, 127.2, 127.0,
126.2, 124.6, 121.2, 112.5, 40.6 ppm. HRMS (ESI+): m/z calcd for
C21H19N2S (M + H)+, 331.1263; found, 331.1259.
1-(4-(2-(Quinolin-2-yl)furan-3-yl)phenyl)ethan-1-one (5ba). Ra-
dial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 20/1). Light brown solid (106 mg, 68%). Melting point =
62−64 °C. FT-IR (ATR, neat): 3040, 1767, 1504, 1309, 1224, 1141,
1054, 951, 821, 736 cm−1. 1H NMR (500 MHz, CDCl3): δ 8.07 (dd, J
= 8.7, 0.8 Hz, 1H), 8.02−7.97 (m, 3H), 7.77 (dd, J = 8.2, 1.4 Hz, 1H),
7.74 (AA′BB′, J = 8.42 Hz, 2H), 7.72−7.65 (m, 2H), 7.61 (d, J = 8.6
Hz, 1H), 7.55−7.47 (m, 1H), 6.71 (d, J = 1.8 Hz, 1H), 2.65 (s, 3H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 197.9, 149.5, 148.6,
148.1, 143.5, 138.9, 136.4, 136.3, 130.0, 129.7, 129.7, 128.4, 127.6,
127.3, 126.8, 125.8, 119.5, 114.4, 26.8 ppm. HRMS (ESI+): m/z calcd
for C21H16NO2 (M + H)+, 314.1176; found, 314.1171.
2-(3-(4-(Trifluoromethyl)phenyl)thiophen-2-yl)quinoline (5ab).
Radial chromatography on silica gel (eluting with petroleum ether/
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Article
1-(4-(2-(Isoquinolin-3-yl)thiophen-3-yl)phenyl)ethan-1-one
(6aa). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 7/1). Dark geen solid (163 mg, 99%). Melting point =
151−153 °C. FT-IR (ATR, neat): 3002, 1676, 1601, 1578, 1404,
112.7, 40.7, 30.9 ppm. HRMS (ESI+): m/z calcd for C21H19N2S (M +
H)+, 331.1263; found, 331.1261.
3-(3-(o-Tolyl)thiophen-2-yl)isoquinoline (6ag). Radial chromatog-
raphy on silica gel (eluting with petroleum ether/EtOAc, 20/1).
Colorless oil (133 mg, 88%). FT-IR (ATR, neat): 3056, 2919, 1622,
1
1359, 1267, 1014, 960, 740 cm−1. H NMR (500 MHz, CDCl3): δ
1
1580, 1455, 1275, 939, 883, 824, 755, 733, 664, 630 cm−1. H NMR
9.23 (s, 1H), 7.98−7.92 (m, 3H), 7.62−7.46 (m, 6H), 7.42 (s, 1H),
7.15 (d, J = 5.1 Hz, 1H), 2.63 (s, 3H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 197.9, 152.6, 146.2, 142.3, 140.6, 138.1, 136.0,
131.0, 130.8, 129.5, 128.9, 127.7, 127.6, 127.5, 127.0, 126.8, 118.5,
26.8 ppm. HRMS (ESI+): m/z calcd for C21H16NOS (M + H)+,
330.0947; found, 330.0944.
(500 MHz, CDCl3): δ 9.19 (s, 1H), 7.88 (dd, J = 8.1, 1.2 Hz, 1H),
7.52 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.49−7.47 (m, 1H), 7.45 (d, J =
5.1 Hz, 1H), 7.38−7.27 (m, 5H), 7.04 (s, 1H), 7.01 (d, J = 5.1 Hz,
1H), 2.11 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.1,
146.7, 140.3, 138.7, 137.6, 136.8, 136.2, 131.5, 130.6, 130.5, 129.8,
128.1, 127.6, 127.4, 127.2, 127.0, 126.5, 126.1, 115.7, 20.1 ppm.
HRMS (ESI+): m/z calcd for C20H16NS (M + H)+, 302.0998; found,
302.1000.
3-(3-(2-Methoxyphenyl)thiophen-2-yl)isoquinoline (6ah). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
5/1). Light yellow solid (127 mg, 80%). Melting point = 145−146
°C. FT-IR (ATR, neat): 3024, 2964, 2829, 1600, 1486, 1459, 1250,
1023, 890, 753, 728, 660 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.20
(s, 1H), 7.93−7.87 (m, 1H), 7.53 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.48
(ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 7.42−7.37
(m, 2H), 7.33−7.29 (m, 2H), 7.11 (d, J = 5.2 Hz, 1H), 7.03−6.97 (m,
2H), 3.62 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 157.1,
151.9, 147.1, 140.7, 136.2, 135.3, 132.1, 131.5, 130.4, 129.3, 127.7,
127.4, 127.0, 126.9, 126.4, 125.7, 121.1, 116.4, 111.5, 55.6 ppm.
HRMS (ESI+): m/z calcd for C20H16NOS (M + H)+, 318.0947;
found, 318.0945.
3-(3-(4-(Trifluoromethyl)phenyl)thiophen-2-yl)isoquinoline
(6ab). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 20/1). White solid (172 mg, 97%). Melting point =
119−122 °C. FT-IR (ATR, neat): 3066, 1624, 1457, 1326, 1159,
1102, 1060, 828, 729, 670 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.24
(s, 1H), 7.94 (dd, J = 8.2, 1.1 Hz, 1H), 7.65−7.60 (m, 4H), 7.58 (dd,
J = 13.0, 1.3 Hz, 1H), 7.56−7.49 (m, 2H), 7.48 (d, J = 5.2 Hz, 1H),
7.39 (s, 1H), 7.14 (d, J = 5.2 Hz, 1H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 152.6, 146.2, 141.0, 140.6, 137.8, 136.0, 130.9 (C−
2
3
F, JC−F = 12.3 Hz), 129.7, 129.5 (C−F, JC−F = 33.0 Hz), 127.7,
127.6, 127.5, 127.0, 126.8, 125.8 (C−F, 2JC−F = 3.8 Hz), 124.4 (C−F,
1JC−F = 272.2 Hz), 118.4 ppm. 19F NMR (471 MHz, CDCl3): δ −62.4
ppm. HRMS (ESI+): m/z calcd for C20H13F3NS (M + H)+, 356.0715;
found, 356.0715.
4-(2-(Isoquinolin-3-yl)thiophen-3-yl)benzonitrile (6ac). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
10/1). Orange solid (111 mg, 71%). Melting point = 120−124 °C.
FT-IR (ATR, neat): 3110, 3027, 2223, 1692, 1622, 1602, 1490, 1273,
3-(2-(Isoquinolin-3-yl)thiophen-3-yl)benzonitrile (6ai). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
7/1). Yellow solid (144 mg, 92%). Melting point = 147−150 °C. FT-
IR (ATR, neat): 3058, 3034, 2226, 1575, 1478, 1016, 875, 825, 727,
1
882, 743 cm−1. H NMR (500 MHz, CDCl3): δ 9.23 (s, 1H), 7.95
(dd, J = 8.1, 1.1 Hz, 1H), 7.66−7.62 (m, 3H), 7.57 (ddd, J = 8.1, 6.9,
1.3 Hz, 1H), 7.55−7.51 (m, 3H), 7.49 (d, J = 5.2 Hz, 1H), 7.40 (s,
1H), 7.14 (d, J = 5.2 Hz, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 152.7, 145.9, 142.1, 141.0, 137.3, 136.0, 132.6, 131.0,
130.6, 130.0, 127.78, 127.7, 127.0, 126.9, 119.1, 118.7, 111.0 ppm.
HRMS (ESI+): m/z calcd for C20H13N2S (M + H)+, 313.0794; found,
313.0794.
3-(3-(p-Tolyl)thiophen-2-yl)isoquinoline (6ad). Radial chromatog-
raphy on silica gel (eluting with petroleum ether/EtOAc, 10/1). Light
brown solid (143 mg, 95%). Melting point = 85−88 °C. FT-IR (ATR,
neat): 3026, 1621, 1542, 1504, 1332, 1023, 885, 815, 736, 694 cm−1.
1H NMR (500 MHz, CDCl3): δ 9.23 (s, 1H), 7.92 (dd, J = 8.1, 1.1
Hz, 1H), 7.58−7.45 (m, 5H), 7.48 (AA′BB′, J = 8.2 Hz, 2H), 7.19
(AA′BB′, J = 8.1 Hz, 2H), 7.11 (d, J = 5.1 Hz, 1 H), 2.41 (s, 3H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.3, 146.8, 139.4,
139.3, 137.3, 136.0, 134.4, 131.6, 130.6, 129.6, 129.1, 127.7, 127.5,
127.1, 127.1, 126.2, 117.8, 21.4 ppm. HRMS (ESI+): m/z calcd for
C20H16NS (M + H)+, 302.0998; found, 302.0997.
1
700, 655, 623, 611 cm−1. H NMR (500 MHz, CDCl3): δ 9.22 (s,
1H), 7.95 (dd, J = 8.1, 1.1 Hz, 1H), 7.74 (m, 1H), 7.66−7.60 (m,
3H), 7.57 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.53 (dd, J = 8.1, 1.1 Hz,
1H), 7.48 (d, J = 5.2 Hz, 1H), 7.47−7.43 (m, 1H), 7.38 (s, 1H), 7.12
(d, J = 5.1 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.7,
145.9, 140.8, 138.7, 136.7, 136.0, 133.9, 132.8, 131.0, 131.0, 130.7,
129.6, 127.8, 127.7, 127.6, 127.0, 126.9, 118.8, 118.4, 113.0 ppm.
HRMS (ESI+): m/z calcd for C20H13N2S (M + H)+, 313.0794; found,
313.0789.
1-(4-(2-(Isoquinolin-3-yl)furan-3-yl)phenyl)ethan-1-one (6ba).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 5/1). Orange oil (92 mg, 59%). FT-IR (ATR, neat): 3056,
2965, 1951, 1761, 1676, 1602, 1488, 1356, 1266, 728 cm−1. 1H NMR
(500 MHz, CDCl3): δ 9.18 (s, 1H), 7.97−7.92 (m, 3H), 7.90 (s, 1H),
7.75−7.72 (m, 1H), 7.68−7.61 (m, 4H), 7.57 (ddd, J = 8.1, 6.8, 1.2
Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 2.62 (s, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 197.9, 152.5, 148.9, 143.8, 142.8, 139.2, 136.2,
135.9, 130.8, 129.3, 128.5, 127.9, 127.8, 127.6, 127.1, 123.9, 117.7,
114.1, 26.7 ppm. HRMS (ESI+): m/z calcd for C21H16NO2 (M + H)+,
314.1176; found, 314.1174.
3-(3-(4-Methoxyphenyl)thiophen-2-yl)isoquinoline (6ae). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
10/1). White solid (152 mg, 96%). Melting point = 110−113 °C. FT-
IR (ATR, neat): 3050, 2992, 2841, 1748, 1606, 1500, 1374, 1241,
3-(3-(4-(Trifluoromethyl)phenyl)furan-2-yl)isoquinoline (6bb).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 20/1). White solid (80 mg, 47%). Melting point = 73−77 °C.
FT-IR (ATR, neat): 3057, 1618, 1575, 1433, 1320, 1160, 1117, 961,
1
1030, 736 cm−1. H NMR (500 MHz, CDCl3): δ 9.23 (s, 1H), 7.91
(dd, J = 8.0, 1.1 Hz, 1H), 7.59−7.47 (m, 3H), 7.45 (s, 1H), 7.42 (d, J
= 5.2 Hz, 1H), 7.36 (AA′BB′, J = 8.0 Hz, 2H), 7.10 (d, J = 5.2 Hz,
1H), 6.92 (AA′BB′, J = 8.1 Hz, 2H), 3.86 (s, 3H) ppm. 13C{1H}
NMR (126 MHz, CDCl3): δ 159.1, 152.3, 146.8, 139.1, 136.1, 131.6,
130.6, 130.4, 129.69, 127.7, 127.5, 127.1, 126.2, 117.8, 114.3, 55.5
ppm. HRMS (ESI+): m/z calcd for C20H16NOS (M + H)+, 318.0947;
found, 318.0950.
1
885, 748 cm−1. H NMR (500 MHz, CDCl3): δ 9.19 (s, 1H), 7.95
(dd, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.76 (dd, J = 8.3,
1.1 Hz, 1H), 7.69−7.65 (m, 3H), 7.65−7.56 (m, 4H), 6.67 (d, J = 1.8
Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.5, 148.7,
3
143.7, 142.8, 137.9, 136.2, 130.9, 129.5, 129.3 (C−F, JC−F = 32.3
2
4-(2-(Isoquinolin-3-yl)thiophen-3-yl)-N,N-dimethylaniline (6af).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 10/1). Yellow solid (148 mg, 89%). Melting point = 112−116
°C. FT-IR (ATR, neat): 3061, 2849, 2103, 1676, 1610, 1508, 1440,
Hz), 128.0, 127.8, 127.6, 127.1, 125.3 (C−F, JC−F = 3.8 Hz), 124.6
1
(C−F, JC−F = 271.8 Hz), 123.6, 117.6, 114.3 ppm. 19F NMR (471
MHz, CDCl3): δ −62.4 ppm. HRMS (ESI+): m/z calcd for
C20H13F3NO (M + H)+, 340.0944; found, 340.0936.
1
1347, 884, 737 cm−1. H NMR (500 MHz, CDCl3): δ 9.23 (s, 1H),
4-(2-(Isoquinolin-3-yl)furan-3-yl)benzonitrile (6bc). Radial chro-
matography on silica gel (eluting with petroleum ether/EtOAc, 10/1).
Light orange solid (89 mg, 60%). Melting point = 132−135 °C. FT-
IR (ATR, neat): 3114, 2222, 1607, 1572, 1452, 1220, 1159, 1048,
7.91 (dd, J = 8.0, 1.1 Hz, 1H), 7.58−7.47 (m, 4H), 7.40 (d, J = 5.1
Hz, 1H), 7.32 (AA′BB′, J = 8.8 Hz, 2H), 7.11 (d, J = 5.1 Hz, 1H),
6.75 (AA′BB′, J = 8.8 Hz, 2H), 3.00 (s, 6H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 152.2, 150.0, 147.1, 139.8, 138.2, 136.1, 131.8,
130.4, 130.1, 129.8, 127.7, 127.4, 127.1, 126.9, 126.0, 125.2, 117.6,
1
836, 749 cm−1. H NMR (500 MHz, CDCl3): δ 9.15 (d, J = 1.0 Hz,
1H), 7.97−7.93 (m, 2H), 7.79 (dd, J = 8.2, 1.1 Hz, 1H), 7.72−7.58
3145
https://dx.doi.org/10.1021/acs.joc.0c01983
J. Org. Chem. 2021, 86, 3138−3151

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(m, 7H), 6.66 (d, J = 1.8 Hz, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 152.4, 149.1, 143.6, 142.9, 139.1, 136.2, 132.0, 131.0,
129.9, 128.0, 127.8, 127.7, 127.1, 123.3, 119.3, 117.7, 114.0, 110.7
ppm. HRMS (ESI+): m/z calcd for C20H13N2O (M + H)+, 297.1022;
found, 297.1016.
3-(3-(4-Methoxyphenyl)furan-2-yl)isoquinoline (6bd). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
10/1). Orange oil (120 mg, 80%). FT-IR (ATR, neat): 2998, 2834,
1945, 1755, 1658, 1623, 1515, 1244, 1159, 747 cm−1. 1H NMR (500
MHz, CDCl3): δ 9.24 (s, 1H), 7.92 (dd, J = 8.1, 1.1 Hz, 1H), 7.83 (d,
J = 1.0 Hz, 1H), 7.67 (dd, J = 8.3, 1.1 Hz, 1H), 7.64−7.58 (m, 2H),
7.53 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.46 (AA′BB′, J = 8.2 Hz, 2H),
6.92 (AA′BB′, J = 8.2 Hz, 2H), 6.61 (d, J = 1.8 Hz, 1H), 3.85 (s, 3H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 159.0, 152.5, 147.5,
144.1, 142.5, 136.2, 130.6, 130.2, 127.7, 127.6, 127.2, 127.0, 126.4,
124.6, 117.2, 114.5, 114.0, 55.4 ppm. HRMS (ESI+): m/z calcd for
C20H16NO2 (M + H)+, 302.1176; found, 302.1168.
4-(2-(Isoquinolin-3-yl)furan-3-yl)-N,N-dimethylaniline (6be). Ra-
dial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 10/1). Orange oil (46 mg, 29%). FT-IR (ATR, neat): 2884,
2802, 1924, 1613, 1521, 1444, 1352, 1319, 1195, 746 cm−1. 1H NMR
(500 MHz, CDCl3): δ 9.26 (s, 1H), 7.93 (dd, J = 8.1, 1.1 Hz, 1H),
7.88 (d, J = 1.1 Hz, 1H), 7.70−7.66 (m, 1H), 7.64−7.56 (m, 2H),
7.53 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.42 (AA′BB′, J = 8.8 Hz, 2H),
6.76 (AA′BB′, J = 8.8 Hz, 2H), 6.61 (d, J = 1.8 Hz, 1H), 3.00 (s, 6H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 152.5, 150.0, 147.1,
144.4, 142.5, 136.2, 130.5, 129.7, 127.7, 127.6, 127.1, 127.1, 125.2,
121.9, 117.1, 114.5, 112.6, 40.7 ppm. HRMS (ESI+): m/z calcd for
C21H19N2O (M + H)+, 315.1492; found, 315.1485.
neat): 3097, 3071, 3019, 2913, 1616, 1585, 1564, 1539, 1420, 1376,
1026, 804, 718 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.24 (d, J = 0.6
Hz, 1H), 7.85−7.78 (m, 3H), 7.55 (ddd, J = 8.1, 6.1, 2.1 Hz, 1H),
7.48 (d, J = 5.1 Hz, 1H), 7.41 (AA′BB′, J = 8.1 Hz, 2H), 7.20−7.16
(m, 3H), 2.42 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
160.2, 158.6, 150.5, 143.8, 137.0, 137.0, 134.3, 134.2, 132.4, 129.6,
128.6, 128.5, 128.1, 127.2, 123.2, 21.5 ppm. HRMS (ESI+): m/z calcd
for C19H15N2S (M + H)+, 303.0900; found, 303.0947.
2-(3-(4-Methoxyphenyl)thiophen-2-yl)quinazoline (7ae). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
10/1). Light yellow solid (141 mg, 89%). Melting point = 119−122
°C. FT-IR (ATR, neat): 3108, 3064, 3031, 2838, 1609, 1585, 1378,
1
1274, 1201, 1024, 821, 747 cm−1. H NMR (500 MHz, CDCl3): δ
9.25 (s, 1H), 7.85−7.78 (m, 3H), 7.55 (ddd, J = 8.1, 6.2, 1.9 Hz, 1H),
7.48 (d, J = 5.1 Hz, 1H), 7.45 (AA′BB′, J = 8.8 Hz, 2H), 7.17 (d, J =
5.1 Hz, 1H), 6.92 (AA′BB′, J = 8.8 Hz, 2H), 3.87 (s, 3H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 160.2, 159.1, 158.6, 150.5,
143.4, 136.7, 134.2, 132.4, 130.9, 129.7, 128.5, 128.1, 127.2, 123.2,
113.2, 55.4 ppm. HRMS (ESI+): m/z calcd for C19H15N2OS (M +
H)+, 319.0900; found, 319.0897.
N,N-Dimethyl-4-(2-(quinazolin-2-yl)thiophen-3-yl)aniline (7af).
Radial chromatography on silica gel (eluting with petroleum ether/
DCM; 1/2). Yellow solid (141 mg, 85%). Melting point = 98−101
°C. FT-IR (ATR, neat): 3062, 2881, 2798, 1608, 1547, 1507, 1417,
1
1395, 1223, 1194, 1166, 815, 802, 722 cm−1. H NMR (500 MHz,
CDCl3): δ 9.26 (d, J = 0.8 Hz, 1H), 7.87−7.78 (m, 3H), 7.54 (ddd, J
= 8.1, 6.8, 1.4 Hz, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.43 (AA′BB′, J =
8.7 Hz, 2H), 7.18 (d, J = 5.1 Hz, 1H), 6.74 (AA′BB′, J = 8.7 Hz, 2H),
3.00 (s, 6H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 160.2, 159.0,
150.6, 150.0, 144.0, 135.6, 134.1, 132.4, 130.6, 128.5, 128.0, 127.2,
127.0, 125.2, 123.1, 111.9, 40.7 ppm. HRMS (ESI+): m/z calcd for
C20H18N3S (M + H)+, 332.1216; found, 332.1214.
2-(2-(Quinazolin-2-yl)thiophen-3-yl)benzonitrile (7ag). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
5/1). Light yellow solid (133 mg, 85%). Melting point = 145−146
°C. FT-IR (ATR, neat): 3111, 3061, 2220, 1420, 1379, 1029, 973,
894, 766, 747, 731 689 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.21 (s
1H), 7.81 (ddd, J = 8.1, 1.5, 0.6 Hz, 1H), 7.79−7.73 (m, 2H), 7.65−
7.61 (m, 1H), 7.57−7.55 (m, 2H), 7.54−7.50 (m, 2H), 7.50−7.47
(m, 1H), 7.17 (d, J = 5.1 Hz, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 160.2, 157.6, 150.2, 142.3, 140.1, 139.3, 134.3, 132.5,
132.1, 131.8, 130.7, 128.7, 128.4, 127.5, 127.4, 127.3, 123.2, 118.7,
113.7 ppm. HRMS (ESI+): m/z calcd for C19H12N3S (M + H)+,
314.0746; found, 314.0744.
1-(4-(2-(Quinazolin-2-yl)thiophen-3-yl)phenyl)ethan-1-one
(7aa). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 7/1). Light yellow solid (162 mg, 98%). Melting point
= 150−154 °C. FT-IR (ATR, neat): 3100, 3081, 3060, 3041, 1671,
1
1562, 1550, 1486, 1420, 1379, 1271, 892, 749, 729 cm−1. H NMR
(500 MHz, CDCl3): δ 9.23 (d, J = 0.8 Hz, 1H), 7.97 (AA′BB′, J = 8.4
Hz, 2H), 7.86−7.80 (m, 2H), 7.73 (dd, J = 8.4, 0.6 Hz, 1H), 7.59
(AA′BB′, J = 8.4 Hz, 2H), 7.56 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.53
(d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 2.66 (s, 3H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 198.2, 160.3, 158.0, 150.3,
142.5, 142.4, 138.5, 135.9, 134.4, 132.0, 130.0, 128.6, 128.6, 128.0,
127.5, 127.3, 123.3, 26.9 ppm. HRMS (ESI+): m/z calcd for
C20H15N2OS (M + H)+, 331.0900; found, 331.0901.
2-(3-(4-(Trifluoromethyl)phenyl)thiophen-2-yl)quinazoline
(7ab). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 7/1). White solid (160 mg, 90%). Melting point =
126−129 °C. FT-IR (ATR, neat): 3065, 3024, 1616, 1586, 1541,
2-(3-(m-Tolyl)thiophen-2-yl)quinazoline (7ah). Radial chroma-
tography on silica gel (eluting with petroleum ether/EtOAc, 10/1).
Colorless oil (122 mg, 81%). FT-IR (ATR, neat): 3018, 2916, 1549,
1
1326, 1277, 1160, 1092, 1061, 830, 731, 666 cm−1. H NMR (500
1
1418, 1375, 935, 804, 736, 700, 661 cm−1. H NMR (500 MHz,
MHz, CDCl3): δ 9.24 (d, J = 0.8 Hz, 1H), 7.86−7.80 (m, 2H), 7.71
(dd, J = 8.4, 1.0 Hz, 1H), 7.66−7.59 (m, 4H), 7.56 (ddd, J = 8.1, 6.9,
1.1 Hz, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 160.3, 158.0, 150.3, 142.2,
141.2 (C−F, 2JC−F = 1.2 Hz), 138.5, 134.5, 132.0, 130.1, 129.3 (C−F,
3JC−F = 23.3 Hz), 128.6, 128.4, 127.5, 127.3, 124.7 (C−F, 2JC−F = 3.9
CDCl3): δ 9.23 (s, 1H), 7.82−7.75 (m, 3H), 7.52 (ddd, J = 8.1, 6.6,
1.4 Hz, 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.36−7.35 (m, 1H), 7.29−7.23
(m, 2H), 7.19−7.16 (m, 2H), 2.37 (s, 3H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 160.1, 158.5, 150.4, 143.9, 137.3, 137.3, 137.1,
134.2, 132.4, 130.3, 128.4, 128.1, 128.0, 127.6, 127.2, 127.2, 126.9,
123.1, 21.6 ppm. HRMS (ESI+): m/z calcd for C19H15N2S (M + H)+,
303.0950; found, 303.0946.
1-(4-(2-(Quinazolin-2-yl)furan-3-yl)phenyl)ethan-1-one (7ba).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 5/3). Light brown solid (138 mg, 88%). Melting point =
152−156 °C. FT-IR (ATR, neat): 3089, 3058, 1732, 1671, 1583,
1483, 1381, 1270, 951, 833, 804, 760, 727 cm−1. 1H NMR (500 MHz,
CDCl3): δ 9.31 (s, 1H), 8.00 (AA′BB′, J = 8.3 Hz, 2H), 7.96 (d, J =
8.7 Hz, 1H), 7.91−7.86 (m, 2H), 7.76 (AA′BB′, J = 8.3 Hz, 2H), 7.73
(m, 1H), 7.60 (m, 1H), 6.72 (s, 1H), 2.66 (s, 3H) ppm. 13C{1H}
NMR (126 MHz, CDCl3): δ 198.0, 160.5, 154.7, 150.4, 147.0, 144.4,
138.9, 136.2, 134.6, 130.0, 129.0, 128.6, 128.0, 127.8, 127.3, 123.6,
115.0, 26.8 ppm. HRMS (ESI+): m/z calcd for C20H15N2O2 (M +
H)+, 315.1128; found, 315.1125.
1
Hz), 124.6 (C−F, JC−F = 272.3 Hz), 123.3 ppm. 19F NMR (471
MHz, CDCl3): δ −62.3 ppm. HRMS (ESI+): m/z calcd for
C19H12F3N2S (M + H)+, 357.0668; found, 357.0671.
4-(2-(Quinazolin-2-yl)thiophen-3-yl)benzonitrile (7ac). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
5/1). Light brown solid (144 mg, 92%). Melting point = 163−166
°C. FT-IR (ATR, neat): 3096, 3055, 2217, 1926, 1671, 1618, 1456,
1423, 1396, 833, 800, 743, 722 cm−1. 1H NMR (500 MHz, CDCl3): δ
9.24 (d, J = 0.8 Hz, 1H), 7.87−7.82 (m, 2H), 7.71−7.65 (m, 3H),
7.62−7.56 (m, 3H), 7.54 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 160.3, 157.7, 150.2,
142.4, 141.6, 138.9, 134.6, 131.7, 131.6, 130.5, 128.9, 128.4, 127.6,
127.3, 123.3, 119.4, 110.8 ppm. HRMS (ESI+): m/z calcd for
C19H12N3S (M + H)+, 314.0746; found, 314.0743.
2-(3-(p-Tolyl)thiophen-2-yl)quinazoline (7ad). Radial chromatog-
raphy on silica gel (eluting with petroleum ether/EtOAc, 10/1). Light
brown solid (128 mg, 85%). Melting point = 87−90 °C. FT-IR (ATR,
2-(3-(4-(Trifluoromethyl)phenyl)furan-2-yl)quinazoline (7bb).
Radial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 10/1). Light yellow solid (148 mg, 87%). Melting point =
3146
https://dx.doi.org/10.1021/acs.joc.0c01983
J. Org. Chem. 2021, 86, 3138−3151

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
102−105 °C. FT-IR (ATR, neat): 3060,1618, 1565, 1552, 1320,
residue was purified by radial chromatography on silica gel to yield the
diarylated products 8−10.
1
1170, 1127, 1106, 1018, 842, 755, 744, 615 cm−1. H NMR (500
4-(4-(4-Acetylphenyl)-5-(quinolin-2-yl)thiophen-2-yl)benzonitrile
(8aa). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 10/1). Yellow solid (172 mg, 80%). Melting point =
98−101 °C. FT-IR (ATR, neat): 3045, 2221, 1675, 1591, 1467, 1354,
MHz, CDCl3): δ 9.31 (d, J = 0.8 Hz, 1H), 7.98−7.94 (m, 1H), 7.91−
7.86 (m, 2H), 7.80−7.75 (m, 2H), 7.73 (d, J = 1.8 Hz, 1H), 7.66 (d, J
= 8.2 Hz, 2H), 7.63−7.58 (m, 1H), 6.71 (d, J = 1.8 Hz, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 160.6, 154.7, 150.4, 147.0,
144.4, 137.6 (C−F, 2JC−F = 1.4 Hz), 134.7, 130.1, 129.6 (C−F, 3JC−F
= 32.5 Hz), 128.8, 128.6, 227.8, 127.3, 124.8 (C−F, 2JC−F = 3.8 Hz),
1
1264, 823, 758, 729 cm−1. H NMR (500 MHz, CDCl3): δ 8.11 (d,
1H), 7.99 (AA′BB′, J = 8.49 Hz, 2H), 7.90 (d, J = 8.7, 0.9 Hz, 1H),
7.80 (AA′BB′, J = 8.52 Hz, 2H), 7.74 (d, 2H), 7.73−7.68 (m, 2H),
7.56−7.51 (m, 3H), 7.47 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 2.65 (s,
3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 197.7, 152.2, 148.4,
143.3, 142.2, 141.2, 140.5, 138.2, 136.7, 136.2, 133.0, 130.2, 129.6,
129.5, 129.0, 128.5, 127.7, 127.3, 127.0, 126.2, 120.5, 118.8, 111.4,
26.8 ppm. HRMS (ESI+): m/z calcd for C28H19N2OS (M + H)+,
431.1213; found, 431.1208.
1
124.5 (C−F, JC−F = 271.3 Hz), 123.6, 115.0 ppm. 19F NMR (471
MHz, CDCl3): δ −62.4 ppm. HRMS (ESI+): m/z calcd for
C19H12F3N2O (M + H)+, 341.0896; found, 341.0896.
4-(2-(Quinazolin-2-yl)furan-3-yl)benzonitrile (7bc). Radial chro-
matography on silica gel (eluting with petroleum ether/EtOAc, 3/1).
Light brown solid (114 mg, 77%). Melting point = 154−158 °C. FT-
IR (ATR, neat): 3121, 3099, 3056, 2230, 1582, 1497, 1378, 1166,
1
892, 839, 804, 752, 650 cm−1. H NMR (500 MHz, CDCl3): δ 9.32
1-(4-(5-(4-Methoxyphenyl)-2-(quinolin-2-yl)thiophen-3-yl)-
phenyl)ethan-1-one (8ab). Radial chromatography on silica gel
(eluting with petroleum ether/EtOAc, 20/1). Yellow solid (170 mg,
78%). Melting point = 72−76 °C. FT-IR (ATR, neat): 2955, 2834,
(s, 1H), 7.96−7.92 (m, 1H), 7.92−7.88 (m, 2H), 7.77 (AA′BB′, J =
8.3 Hz, 2H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (AA′BB′, J = 8.3 Hz, 2H),
7.62 (ddd, J = 8.8, 5.6, 2.2 Hz, 1H), 6.70 (d, J = 1.8 Hz, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 160.6, 154.5, 150.4, 147.1,
144.6, 138.9, 134.8, 131.7, 130.6, 128.6, 128.3, 127.9, 127.4, 123.7,
119.3, 114.8, 111.2 ppm. HRMS (ESI+): m/z calcd for C19H12N3O
(M + H)+, 298.0975; found, 298.0975.
2-(3-(p-Tolyl)furan-2-yl)quinazoline (7bd). Radial chromatogra-
phy on silica gel (eluting with petroleum ether/EtOAc, 5/1). Light
brown solid (118 mg, 83%). Melting point = 69−74 °C. FT-IR (ATR,
neat): 3064, 3015, 2960, 2917, 2222, 1617, 1563, 1515, 1415, 813,
804, 753, 721 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.29 (d, J = 0.6
Hz, 1H), 7.98 (dd, J = 8.4, 0.8 Hz, 1H), 7.87−7.81 (m, 2H), 7.68 (d, J
= 1.8 Hz, 1H), 7.59−7.53 (m, 3H), 7.21 (d, J = 7.9 Hz, 2H), 6.68 (d,
J = 1.8 Hz, 1H), 2.41 (s, 1H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 160.4, 155.1, 150.5, 146.1, 144.0, 137.4, 134.3, 130.7,
130.2, 129.6, 128.6, 128.5, 127.3, 127.2, 123.4, 115.3, 21.4 ppm.
HRMS (ESI+): m/z calcd for C19H15N2O (M + H)+, 287.1179;
found, 287.1178.
1
1678, 1593, 1516, 1464, 1248, 1110, 820, 692 cm−1. H NMR (500
MHz, CDCl3): δ 8.10 (d, 1H), 7.97 (AA′BB′, J = 8.43 Hz, 2H), 7.85
(d, J = 8.7, 0.8 Hz, 1H), 7.74−7.68 (m, 2H), 7.65 (AA′BB′, J = 8.80
Hz, 2H), 7.54 (AA′BB′, J = 8.48 Hz, 2H), 7.51−7.45 (m, 1H), 7.26
(d, J = 3.0 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.96 (AA′BB′, J = 8.78
Hz, 2H), 3.85 (s, 3H), 2.64 (s, 3H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 197.9, 159.9, 152.9, 148.4, 146.2, 141.9, 140.3, 138.8,
136.3, 135.9, 130.0, 129.6, 129.4, 128.9, 127.6, 127.3, 127.0, 126.7,
126.6, 125.7, 120.7, 114.6, 55.6, 26.8 ppm. HRMS (ESI+): m/z calcd
for C28H22NO2S (M + H)+, 436.1366; found, 436.1362.
4-(5-(Quinolin-2-yl)-4-(4-(trifluoromethyl)phenyl)thiophen-2-yl)-
benzonitrile (8ac). Radial chromatography on silica gel (eluting with
petroleum ether/EtOAc, 50/1). Yellow solid (185 mg, 81%). Melting
point = 67−71 °C. FT-IR (ATR, neat): 3055, 2224, 1592, 1426,
1321, 1119, 1064, 958, 824, 708 cm−1. 1H NMR (500 MHz, CDCl3):
δ 8.11 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.1
Hz, 2H), 7.78−7.69 (m, 4H), 7.67 (d, J = 8.0 Hz, 2H), 7.60−7.51 (m,
3H), 7.45 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 152.0, 148.3, 143.4, 142.1, 140.1, 140.0 (C−F, 2JC−F
2-(3-(4-Methoxyphenyl)furan-2-yl)quinazoline (7be). Radial
chromatography on silica gel (eluting with petroleum ether/EtOAc,
5/1). Light brown solid (133 mg, 88%). Melting point = 133−136
°C. FT-IR (ATR, neat): 3135, 3112, 3020, 2930, 2836, 1613, 1583,
1514, 1485, 1253, 1026, 819, 764 cm−1. 1H NMR (500 MHz,
CDCl3): δ 9.32 (d, J = 0.7 Hz, 1H), 8.00−7.97 (m, 1H), 7.88−7.84
(m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.63 (AA′BB′, J = 8.9 Hz, 2H),
7.60−7.56 (m, 1H), 6.95 (AA′BB′, J = 8.9 Hz, 2H), 6.68 (d, J = 1.8
Hz, 1H), 3.87 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
160.5, 159.3, 155.2, 150.6, 146.0, 144.1, 134.4, 131.0, 130.1, 128.6,
127.4, 127.3, 126.1, 123.5, 115.3, 113.4, 55.4 ppm. HRMS (ESI+): m/
z calcd for C19H15N2O2 (M + H)+, 303.1128; found, 303.1126.
N,N-Dimethyl-4-(2-(quinazolin-2-yl)furan-3-yl)aniline (7bf). Ra-
dial chromatography on silica gel (eluting with petroleum ether/
EtOAc, 5/1). Light brown solid (128 mg, 81%). Melting point = 50−
53 °C. FT-IR (ATR, neat): 3061, 2883, 2802, 2220, 1613, 1582,
= 1.3 Hz), 138.1, 136.3, 133.0, 130.3 (C−F, 3JC−F = 32.3 Hz), 130.3,
2
129.7, 129.4, 128.6, 127.7, 127.2, 127.0, 126.2, 125.9 (C−F, JC−F
=
1
3.8 Hz), 124.2 (C−F, JC−F = 272.8 Hz), 120.4, 118.8, 111.4. ppm.
19F NMR (471 MHz, CDCl3): δ −62.5 ppm. HRMS (ESI+): m/z
calcd for C27H16F3N2S (M + H)+, 457.0981; found, 457.0975.
2-(5-(p-Tolyl)-3-(4-(trifluoromethyl)phenyl)thiophen-2-yl)-
quinoline (8ad). Radial chromatography on silica gel (eluting with
petroleum ether/DCM, 3/1). Yellow solid (202 mg, 91%). Melting
point = 167−169 °C. FT-IR (ATR, neat): 2917, 1614, 1468, 1410,
1237, 1102, 932, 812, 750, 695 cm−1. 1H NMR (500 MHz, CDCl3): δ
8.11 (d, J = 8.4, 1.0 Hz, 1H), 7.89 (d, J = 8.7, 0.8 Hz, 1H), 7.76−7.69
(m, 2H), 7.67−7.60 (m, 4H), 7.57 (d, 2H), 7.53−7.49 (m, 1H), 7.32
(s, 1H), 7.24 (d, 2H), 7.09 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 152.8, 148.4, 146.4, 140.7 (C−
1
1549, 1500, 1446, 1166, 1011, 890, 752, 720 cm−1. H NMR (500
2
F, JC−F = 1.4 Hz), 139.9, 139.2, 138.4, 136.0, 131.1, 130.0, 129.9,
3
MHz, CDCl3): δ 9.32 (d, J = 0.5 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H),
7.88−7.83 (m, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.62 (AA′BB′, J = 8.9
Hz, 2H), 7.58−7.54 (m, 1H), 6.77 (AA′BB′, J = 8.9 Hz, 2H), 6.69 (d,
J = 1.8 Hz, 1H), 3.01 (s, 6H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 160.4, 155.5, 150.6, 150.2, 145.5, 144.1, 134.3, 130.7,
130.6, 128.6, 127.2, 127.2, 123.4, 121.4, 115.2, 111.9, 40.7 ppm.
HRMS (ESI+): m/z calcd for C20H18N3O (M + H)+, 316.1444;
found, 316.1442.
General Method for Palladium-Catalyzed C−H Arylation. A
mixture of the monoarylated substrates 5−7 (0.50 mmol), aryl
bromide 4 (1.00 mmol), PdCl(C3H5)(dppe) (0.05 mmol, 29 mg) or
Pd(OAc)2 (0.05 mmol, 11 mg)/PPh3 (0.10 mmol, 26 mg), and
K2CO3 (1.50 mmol, 207 mg) in 1,4-dioxane (2 mL) was stirred for 48
h at 130 °C under argon in a sealed tube. The mixture was then
cooled to room temperature, and DCM (10 mL) was added, after
which the inorganic salts were filtered off and washed with DCM (5
mL). The filtrate was concentrated under reduced pressure, and the
129.9 (C−F, JC−F = 32.3 Hz), 129.7, 129.4, 127.6, 127.0, 126.7,
126.3, 125.9, 125.8 (C−F, 2JC−F = 3.8 Hz), 124.4 (C−F, 1JC−F = 272.7
Hz), 120.6, 21.4 ppm. 19F NMR (471 MHz, CDCl3): δ −62.4 ppm.
HRMS (ESI+): m/z calcd for C27H19F3NS (M + H)+, 446.1185;
found, 446.1182.
1-(4-(5-(Quinolin-2-yl)-4-(4-(trifluoromethyl)phenyl)thiophen-2-
yl)phenyl)ethan-1-one (8ae). Radial chromatography on silica gel
(eluting with petroleum ether/EtOAc, 10/1). Yellow solid (187 mg,
79%). Melting point = 167−169 °C. FT-IR (ATR, neat): 3052, 1556,
1
1467, 1412, 1269, 1163, 884, 833, 768, 668 cm−1. H NMR (500
MHz, CDCl3): δ 8.12 (d, J = 8.2, 1.0 Hz, 1H), 8.02 (AA′BB′, J = 8.53
Hz, 2H), 7.92 (d, J = 8.7, 0.8 Hz, 1H), 7.81 (AA′BB′, J = 8.65 Hz,
2H), 7.78−7.70 (m, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.57 (d, 2H),
7.56−7.50 (m, 1H), 7.47 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 2.64 (s,
3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 197.4, 152.3, 148.4,
144.4, 141.5, 140.3 (C−F, 2JC−F = 1.4 Hz), 140.1, 138.2, 136.4, 136.2,
3
130.2, 130.2 (C−F, JC−F = 33.0 Hz), 129.7, 129.5, 129.4, 128.2,
3147
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J. Org. Chem. 2021, 86, 3138−3151

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Article
127.7, 127.2, 126.9, 125.9, (C−F, 2JC−F = 3.7 Hz), 128.8, 124.3 (C−F,
1JC−F = 272.3 Hz), 120.5, 26.8 ppm. 19F NMR (471 MHz, CDCl3): δ
HRMS (ESI+): m/z calcd for C27H22NOS (M + H)+, 408.1417;
found, 408.1411.
−62.5 ppm. HRMS (ESI+): m/z calcd for C28H19F3NOS (M + H)+,
474.1134; found, 474.1130.
3-(2-(Isoquinolin-3-yl)-5-(m-tolyl)thiophen-3-yl)benzonitrile
(9ad). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 7/1). Yellow solid (121 mg, 60%). Melting point =
168−170 °C. FT-IR (ATR, neat): 3052, 2918, 2223, 1621, 1580,
1479, 1275, 801, 781, 687 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.23
(s, 1H), 7.95 (dd, J = 8.1, 1.1 Hz, 1H), 7.81−7.80 (m, 1H), 7.71−
7.69 (m, 1H), 7.68−7.65 (m, 1H), 7.62 (ddd, J = 8.1, 6.9, 1.3 Hz,
1H), 7.56 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.54−7.46 (m, 4H), 7.37 (s,
1H), 7.33−7.30 (m, 2H), 7.17−7.14 (m, 1H), 2.42 (s, 3H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 152.7, 145.9, 145.4, 139.6,
138.9, 138.8, 137.4, 136.0, 133.9, 133.8, 132.8, 131.2, 131.0, 129.7,
129.1, 129.1, 127.8, 127.7, 127.6, 126.9, 126.6, 126.6, 123.0, 118.8,
118.0, 113.1, 21.6 ppm. HRMS (ESI+): m/z calcd for C27H19N2S (M
+ H)+, 403.1263; found, 403.1260.
4-(4-(4-Acetylphenyl)-5-(quinolin-2-yl)furan-2-yl)benzonitrile
(8ba). Radial chromatography on silica gel (eluting with petroleum
ether/DCM, 1/1). Yellow solid (147 mg, 71%). Melting point =
237−242 °C. FT-IR (ATR, neat): 3108, 2221, 1677, 1594, 1416,
1307, 1143, 967, 823, 758 cm−1. 1H NMR (500 MHz, CDCl3): δ 8.16
(d, J = 8.7, 0.8 Hz, 1H), 8.02 (AA′BB′, J = 8.54 Hz, 2H), 7.97−7.89
(m, 3H), 7.86−7.78 (m, 4H), 7.74 (AA′BB′, J = 8.53 Hz, 2H), 7.72−
7.67 (m, 1H), 7.57−7.48 (m, 1H), 7.12 (s, 1H), 2.67 (s, 3H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 197.9, 152.1, 149.3, 149.0,
148.0, 138.1, 136.6, 136.5, 133.8, 132.9, 130.1, 129.8, 129.7, 128.3,
128.1, 127.7, 127.4, 127.1, 124.6, 119.4, 118.9, 112.5, 111.3, 26.9
ppm. HRMS (ESI+): m/z calcd for C28H19N2O2 (M + H)+, 415.1441;
found, 415.1439.
4-(4-(4-Acetylphenyl)-5-(isoquinolin-3-yl)furan-2-yl)benzonitrile
(9ba). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 3/1). Yellow solid (180 mg, 87%). Melting point =
186−190 °C. FT-IR (ATR, neat): 3049, 2227, 1925, 1672, 1601,
1-(4-(5-(4-(Dimethylamino)phenyl)-2-(quinolin-2-yl)furan-3-yl)-
phenyl)ethan-1-one (8bb). Radial chromatography on silica gel
(eluting with petroleum ether/EtOAc, 10/1). Orange solid (158 mg,
73%). Melting point = 210−214 °C. FT-IR (ATR, neat): 3124, 2893,
1
1560, 1352, 1275, 813, 748 cm−1. H NMR (500 MHz, CDCl3): δ
1
1676, 1592, 1484, 1258, 1126, 867, 834, 758 cm−1. H NMR (500
9.18 (s, 1H), 8.04 (s, 1H), 8.01−7.95 (m, 4H), 7.94−7.90 (m, 2H),
7.85−7.81 (m, 1H), 7.74−7.67 (m, 4H), 7.62 (ddd, J = 8.1, 6.9, 1.2
Hz, 1H), 7.09 (s, 1H), 2.65 (s, 3H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 197.8, 152.6, 151.6, 149.7, 143.3, 138.5, 136.2, 136.1,
134.0, 132.8, 131.1, 129.4, 128.5, 128.1, 127.9, 127.9, 127.2, 126.5,
124.4, 119.0, 118.1, 112.4, 111.0, 26.8 ppm. HRMS (ESI+): m/z calcd
for C28H19N2O2 (M + H)+, 415.1441; found, 415.1439.
MHz, CDCl3): δ 8.10 (d, J = 8.8, 0.9 Hz, 1H), 8.01 (AA′BB′, J = 8.57
Hz, 2H), 7.91−7.86 (m, 3H), 7.83 (d, J = 8.7 Hz, 1H), 7.78−7.70 (m,
3H), 7.68−7.62 (m, 1H), 7.51−7.44 (m, 1H), 6.79 (AA′BB′, J = 8.96
Hz, 2H), 6.77 (s, 1H), 3.03 (s, 6H), 2.67 (s, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 198.1, 155.6, 150.5, 149.9, 148.0, 146.6, 139.3,
136.2, 136.1, 129.8, 129.7, 129.5, 128.3, 128.1, 127.5, 127.1, 126.3,
125.8, 119.3, 118.4, 112.3, 107.0, 40.5, 26.9 ppm. HRMS (ESI+): m/z
calcd for C29H25N2O2 (M + H)+, 433.1911; found, 433.1908.
4-(4-(4-Acetylphenyl)-5-(isoquinolin-3-yl)thiophen-2-yl)-
benzonitrile (9aa). Radial chromatography on silica gel (eluting with
petroleum ether/EtOAc, 5/1). Yellow solid (200 mg, 93%). Melting
point = 239−241 °C. FT-IR (ATR, neat): 3051, 2291, 2220, 1764,
1-(4-(2-(Isoquinolin-3-yl)-5-(4-(trifluoromethyl)phenyl)furan-3-
yl)phenyl)ethan-1-one (9bb). Radial chromatography on silica gel
(eluting with petroleum ether/EtOAc, 3/1). Yellow solid (158 mg,
69%). Melting point = 193−195 °C. FT-IR (ATR, neat): 1674, 1616,
1
1404, 1329, 1269, 1165, 1107, 1050, 841, 756 cm−1. H NMR (500
MHz, CDCl3): δ 9.18 (s, 1H), 8.05 (s, 2H), 8.01−7.91 (m, 4H), 7.83
(d, J = 8.3 Hz, 1H), 7.74−7.67 (m, 5H), 7.61 (ddd, J = 8.0, 6.9, 1.1
Hz, 1H), 7.05 (s, 1H), 2.65 (s, 3H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 197.9, 152.5, 152.2, 149.2, 143.5, 138.7, 136.2 (C−F, 2JC−F
= 9.5 Hz), 133.3, 131.0, 129.7 (C−F, 3JC−F = 32.5 Hz), 129.4, 128.4,
128.1, 127.9, 127.8, 127.2, 126.3, 126.0 (C−F, 2JC−F = 3.9 Hz), 124.4
1
1672, 1621, 1598, 1269, 820 cm−1. H NMR (500 MHz, CDCl3): δ
9.24 (s, 1H), 8.02 (AA′BB′, J = 8.3 Hz, 2H), 7.95 (dd, J = 8.2, 1.2 Hz,
1H), 7.79 (AA′BB′, J = 8.2 Hz, 2H), 7.70 (AA′BB′, J = 8.1 Hz, 2H),
7.64−7.54 (m, 4H), 7.48 (dd, J = 8.1, 1.2 Hz, 1H), 7.44 (s, 1H), 7.41
(s, 1H), 2.66 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
197.8, 152.7, 145.4, 142.2, 142.2, 141.7, 139.2, 138.3, 136.5, 135.9,
133.0, 131.1, 129.5, 129.1, 128.9, 128.1, 127.8, 127.1, 125.9, 118.9,
118.3, 111.1, 26.9 ppm. HRMS (ESI+): m/z calcd for C28H19N2OS
(M + H)+, 431.1213; found, 431.1209.
1
(C−F, JC−F = 271.7 Hz), 124.3, 117.9, 111.4, 26.8 ppm. 19F NMR
(471 MHz, CDCl3): δ −62.5 ppm. HRMS (ESI+): m/z calcd for
C28H19F3NO2 (M + H)+, 458.1362; found, 458.1358.
4-(4-(4-Acetylphenyl)-5-(quinazolin-2-yl)thiophen-2-yl)-
benzonitrile (10aa). Radial chromatography on silica gel (eluting
with petroleum ether/DCM, 1/5). Yellow solid (142 mg, 66%).
Melting point = >250 °C. FT-IR (ATR, neat): 3069, 3051, 2224,
1-(4-(2-(Isoquinolin-3-yl)-5-(4-(trifluoromethyl)phenyl)thiophen-
3-yl)phenyl)ethan-1-one (9ab). Radial chromatography on silica gel
(eluting with petroleum ether/EtOAc, 5/1). Yellow solid (222 mg,
94%). Melting point = 175−180 °C. FT-IR (ATR, neat): 3063, 1672,
1605, 1580, 1414, 1320, 1270, 1109, 1065, 832 cm−1. 1H NMR (500
MHz, CDCl3): δ 9.25 (s, 1H), 8.01 (AA′BB′, J = 8.3 Hz, 2H), 7.95
(dd, J = 8.0, 1.2 Hz, 1H), 7.82−7.79 (m, 2H), 7.67 (AA′BB′, J = 8.2
Hz, 2H), 7.63−7.54 (m, 4H), 7.48 (dd, J = 8.1, 1.2 Hz, 1H), 7.42 (d, J
= 2.5 Hz, 2H), 2.66 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3):
δ 197.8, 152.7, 145.6, 142.9, 141.9, 141.2, 139.1, 137.4, 136.4, 135.9,
1
1670, 1600, 1584, 1466, 1274, 1178, 863, 819, 730, 717 cm−1. H
NMR (500 MHz, CDCl3): δ 9.25 (d, J = 0.8 Hz, 1H), 8.01 (AA′BB′, J
= 8.3 Hz, 2H), 7.88−7.84 (m, 2H), 7.82 (AA′BB′, J = 8.5 Hz, 2H),
7.75 (d, J = 1.0 Hz, 1H), 7.72 (AA′BB′, J = 8.5 Hz, 2H), 7.64
(AA′BB′, J = 8.3 Hz, 2H), 7.59 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.49
(s, 1H), 2.68 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
198.1, 160.3, 157.5, 150.3, 143.7, 143.6, 142.0, 139.6, 138.1, 136.2,
134.7, 133.0, 129.9, 129.7, 128.5, 128.0, 127.8, 127.4, 126.3, 123.4,
118.8, 111.6, 26.9 ppm. HRMS (ESI+): m/z calcd for C27H18N3OS
(M + H)+, 432.1165; found, 432.1163.
132.6 (C−F, 2JC−F = 10.3 Hz), 131.0, 129.8 (C−F, 3JC−F = 32.8 Hz),
2
129.5, 129.1, 128.2, 127.8, 127.8, 127.7, 127.1, 126.2 (C−F, JC−F
=
3.8 Hz), 125.8, 124.3 (C−F, JC−F = 272.2 Hz) 118.3, 26.9 ppm. 19F
NMR (471 MHz, CDCl3): δ −62.6 ppm. HRMS (ESI+): m/z calcd
for C28H19F3NOS (M + H)+, 474.1134; found, 474.1132.
1
1-(4-(2-(Quinazolin-2-yl)-5-(p-tolyl)thiophen-3-yl)phenyl)ethan-
1-one (10ab). Radial chromatography on silica gel (eluting with
petroleum ether/DCM, 1/5). Yellow solid (174 mg, 83%). Melting
point = 157−160 °C. FT-IR (ATR, neat): 3075, 3055, 3010, 2914,
3-(3-(2-Methoxyphenyl)-5-(m-tolyl)thiophen-2-yl)isoquinoline
(9ac). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 10/1). Yellow solid (147 mg, 72%). Melting point =
156−157 °C. FT-IR (ATR, neat): 3008, 2834, 1733, 1459, 1274,
1025, 780, 753, 692, 674 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.21
(s, 1H), 7.90 (dd, J = 8.1, 1.1 Hz, 1H), 7.58−7.52 (m, 3H), 7.48
(ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.45−7.39 (m, 2H), 7.38 (dd, J = 7.4,
1.8 Hz, 1H), 7.33 (s, 1H), 7.31−7.27 (m, 2H), 7.13−7.10 (m, 1H),
7.06−7.01 (m, 2H), 3.65 (s, 3H), 2.40 (s, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 157.1, 151.9, 147.0, 143.8, 139.8, 138.6, 136.1,
136.1, 134.4, 131.4, 130.5, 129.5, 128.9, 128.5, 128.1, 127.7, 127.4,
127.0, 126.8, 126.6, 126.6, 122.9, 121.1, 116.2, 111.5, 55.7, 21.6 ppm.
1
2854, 1737, 1672, 1584, 1465, 1352, 1239, 799, 752, 716 cm−1. H
NMR (500 MHz, CDCl3): δ 9.22 (d, J = 0.8 Hz, 1H), 8.00 (AA′BB′, J
= 8.5 Hz, 2H), 7.85−7.79 (m, 2H), 7.74−7.70 (m, 1H), 7.67−7.62
(m, 4H), 7.55 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.36 (s, 1H), 7.26−7.22
(m, 2H), 2.67 (s, 3H), 2.40 (s, 3H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 198.2, 160.2, 158.0, 150.4, 146.9, 143.4, 142.7, 138.6,
136.7, 135.9, 134.4, 131.0, 130.0, 129.9, 128.4, 127.9, 127.5, 127.3,
127.3, 125.9, 123.2, 26.9, 21.4 ppm. HRMS (ESI+): m/z calcd for
C27H21N2OS (M + H)+, 421.1369; found, 421.1359.
3148
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Article
1-(4-(2-(Quinazolin-2-yl)-5-(4-(trifluoromethyl)phenyl)thiophen-
3-yl)phenyl)ethan-1-one (10ac). Radial chromatography on silica gel
(eluting with petroleum ether/DCM, 1/3). Yellow solid (220 mg,
93%). Melting point = 168−171 °C. FT-IR (ATR, neat): 3067, 3033,
cymene)Cl2]2 (0.05 mmol, 31 mg), PPh3 (0.10 mmol, 26 mg or 0.20
mmol, 52 mg), KOPiv (0.20 mmol, 28 mg), and K2CO3 (2.50 mmol,
345 mg) in 1,4-dioxane (2 mL) was stirred for 24 h at 140 °C under
argon in a sealed tube. The mixture was then cooled to room
temperature, and the corresponding aryl bromide 4 (1.00 mmol) and
PdCl(C3H5)(dppe) (0.05 mmol, 29 mg) or Pd(OAc)2 (0.05 mmol,
11 mg) were added. The mixture was further stirred for 48 h at 130
°C under argon in a sealed tube. After completion of the second
arylation, the mixture was cooled to room temperature and DCM (10
mL) was added, after which the inorganic salts were filtered off and
washed with DCM (5 mL). The filtrate was concentrated under
reduced pressure, and the residue was purified by radial chromatog-
raphy on silica gel to yield the diarylated products 8−10.
1
2998, 2960, 1739, 1673, 1326, 1098, 1068, 820, 757, 717 cm−1. H
NMR (500 MHz, CDCl3): δ 9.24 (d, J = 0.8 Hz, 1H), 8.01 (AA′BB′, J
= 8.3 Hz, 2H), 7.85−7.81 (m, 4H), 7.75−7.72 (m, 1H), 7.71−7.67
(m, 2H), 7.65 (AA′BB′, J = 8.3 Hz, 2H), 7.58 (ddd, J = 8.1, 6.9, 1.2
Hz, 1H), 7.47 (s, 1H), 2.68 (s, 3H) ppm. 13C{1H} NMR (126 MHz,
CDCl3): δ 198.1, 160.3, 157.6, 150.3, 144.5, 143.5, 142.2, 138.8,
137.2 (C−F, 2JC−F = 1.4 Hz), 136.1, 134.6, 130.2 (C−F, 3JC−F = 32.9
Hz), 130.0, 129.1, 128.5, 128.0, 127.7, 127.3, 126.2 (C−F, 2JC−F = 4.0
1
Hz), 126.1,124.2 (C−F, JC−F = 272.3 Hz), 123.3, 26.9 ppm. 19F
NMR (471 MHz, CDCl3): δ −62.6 ppm. HRMS (ESI+): m/z calcd
Scale-up Synthesis of Compound 10ac According to the
General Method for One-Pot Dual Metal Ruthenium/Palla-
dium-Catalyzed C−H Arylation. A mixture of the substrate 3a
(7.07 mmol, 1.50 g), aryl bromide 4a (7.07 mmol, 1.41 g), [Ru(p-
cymene)Cl2]2 (0.71 mmol, 433 mg), PPh3 (1.41 mmol, 370 mg),
KOPiv (2.83 mmol, 396 mg), and K2CO3 (35.35 mmol, 4.88 g) in
1,4-dioxane (15 mL) was stirred for 24 h at 140 °C under argon in a
sealed tube. The mixture was then cooled to room temperature, and
the corresponding aryl bromide 4b (14.14 mmol, 1.98 mL, d = 1.61
g/mL) and PdCl(C3H5)(dppe) (0.71 mmol, 413 mg) was added. The
mixture was further stirred for 48 h at 130 °C under argon in a sealed
tube. After completion of the second arylation, the mixture was cooled
to room temperature and DCM (20 mL) was added, after which the
inorganic salts were filtered off and washed with DCM (10 mL). The
filtrate was concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel eluting with
petroleum ether/DCM (1/3) to yield the diarylated product 10ac
as a yellow solid (2.68 g, 80%).
for C27H18F3N2OS (M + H)+, 475.1086; found, 475.1085.
2-(5-(2-Methoxyphenyl)-2-(quinazolin-2-yl)thiophen-3-yl)-
benzonitrile (10ad). Radial chromatography on silica gel (eluting
with petroleum ether/EtOAc, 5/1). Yellow solid (193 mg, 92%).
Melting point = 195−197 °C. FT-IR (ATR, neat): 2941, 2223, 1616,
1
1426, 1281, 1020, 863, 760, 746, 676 cm−1. H NMR (500 MHz,
CDCl3): δ 9.22 (s, 1H), 7.81−7.73 (m, 4H), 7.66−7.63 (m, 1H),
7.60−7.54 (m, 3H), 7.53−7.47 (m, 2H), 7.33 (ddd, J = 8.6, 7.4, 1.7
Hz, 1H), 7.06−7.01 (m, 2H), 4.01 (s, 3H) ppm. 13C{1H} NMR (126
MHz, CDCl3): δ 160.1, 157.9, 156.2, 150.3, 142.7, 142.3, 139.2,
138.8, 134.2, 132.5, 132.1, 130.7, 129.9, 129.4, 128.4, 128.4, 127.4,
127.3, 127.1, 123.1, 122.6, 121.1, 118.8, 113.8, 111.8, 55.8 ppm.
HRMS (ESI+): m/z calcd for C26H18N3OS (M + H)+, 420.1165;
found, 420.1160.
2-(5-(Quinazolin-2-yl)-4-(m-tolyl)thiophen-2-yl)benzonitrile
(10ae). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 5/1). White solid (69 mg, 34%). Melting point = 177−
180 °C. FT-IR (ATR, neat): 2913, 2220, 1616, 1585, 1565, 1467,
1030, 756, 696, 670, 654 cm−1. 1H NMR (500 MHz, CDCl3): δ 9.26
(s, 1H), 7.87−7.82 (m, 2H), 7.82−7.76 (m, 2H), 7.73 (s, 1H), 7.67−
6.64 (m, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.46−7.42 (m,
2H), 7.36−7.32 (m, 1H), 7.29−7.25 (m, 2H), 7.19 (d, J = 7.6 Hz,
1H), 2.39 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 160.2,
158.1, 150.4, 144.8, 141.0, 138.87, 137.5, 137.3, 136.6, 134.6, 134.4,
133.2, 132.6, 130.3, 129.7, 128.6, 128.4, 128.2, 127.8, 127.5, 127.3,
127.0, 123.3, 118.8, 110.2, 21.7 ppm. HRMS (ESI+): m/z calcd for
C26H18N3S (M + H)+, 404.1216; found, 404.1212.
Synthesis of Ru-Complex A.44 A solution of [RuCl2(p-
cymene)]2 (0.25 mmol, 153 mg), 2-(thiophen-2-yl)quinazoline (3a)
(0.50 mmol, 106 mg), and KOAc (1.00 mmol, 98 mg) in MeOH (4
mL) was stirred at room temperature for 72 h, after which an orange
solid began to precipitate. The solid was filtered off and washed with
MeOH (3 × 3 mL) and dried at room temperature overnight. Orange
solid (205 mg, 99%). Melting point = >250 °C. FT-IR (ATR, neat):
3039, 2963, 2869, 1614, 1585, 1477, 1416, 1371, 1031, 989, 862, 797,
1
783, 738 cm−1. H NMR (500 MHz, CDCl3): δ 9.91 (d, J = 0.8 Hz,
1H), 7.92−7.88 (m, 1H), 7.85−7.77 (m, 2H), 7.64 (q, J = 4.7 Hz,
2H), 7.50 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 5.71 (dd, J = 5.9, 1.2 Hz,
1H), 5.63 (dd, J = 5.9, 1.2 Hz, 1H), 5.28 (dd, J = 5.8, 1.2 Hz, 1H),
5.15 (dd, J = 5.8, 1.3 Hz, 1H), 2.55−2.45 (m, 1H), 2.07 (s, 3H), 1.04
(d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 181.9, 164.9, 164.0, 150.7, 136.6, 135.6, 134.8,
131.6, 127.8, 127.2, 126.5, 121.5, 101.7, 100.9, 89.2, 88.1, 83.5, 82.2,
31.1, 22.8, 21.9, 19.0 ppm. HRMS (ESI+): m/z calcd for
C22H22ClN2Ru96S (M + H)+, 477.0263; found, 477.0260.
4-(4-(4-Acetylphenyl)-5-(quinazolin-2-yl)furan-2-yl)benzonitrile
(10ba). Radial chromatography on silica gel (eluting with petroleum
ether/EtOAc, 5/1). Light yellow solid (106 mg, 51%). Melting point
= 147−151 °C. FT-IR (ATR, neat): 3054, 2925, 2226, 1671, 1606,
1
1484, 1406, 1356, 1266, 825, 760, 724 cm−1. H NMR (500 MHz,
CDCl3): δ 9.36 (d, J = 0.7 Hz, 1H), 8.05−7.99 (m, 4H), 7.96−7.89
(m, 3H), 7.78 (AA′BB′, J = 8.5 Hz, 2H), 7.75 (AA′BB′, J = 8.5 Hz,
2H), 7.64 (ddd, J = 8.1, 6.6, 1.5 Hz, 1H), 7.12 (s, 1H), 2.68 (s, 3H)
ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 198.0, 160.6, 154.4,
153.0, 150.5, 147.8, 138.4, 136.5, 134.7, 133.7, 132.8, 131.1, 129.9,
128.7, 128.1, 128.1, 127.4, 125.1, 123.7, 118.9, 112.8, 111.6, 26.9
ppm. HRMS (ESI+): m/z calcd for C27H18N3O2 (M + H)+, 416.1394;
found, 416.1393.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01983.
■
sı
1-(4-(2-(Quinazolin-2-yl)-5-(p-tolyl)furan-3-yl)phenyl)ethan-1-
one (10bb). Radial chromatography on silica gel (eluting with
petroleum ether/DCM, 1/3). Yellow solid (57 mg, 28%). Melting
point = 70−75 °C. FT-IR (ATR, neat): 3058, 2959, 2921, 2856,
Copies of 1H, 13C, and 19F NMR spectra for the
reported compounds; single crystal X-ray diffraction data
for 8ba, 9ab, and Ru-complex A; optimization of Ru-
catalyzed C−H arylation of 1a with 4a; competition
experiments (PDF)
1
2246, 1677, 1606, 1484, 1293, 908, 807, 762, 725 cm−1. H NMR
(500 MHz, CDCl3): δ 9.33 (d, J = 0.8 Hz, 1H), 8.04−7.99 (m, 2H),
7.93−7.90 (m, 1H), 7.90−7.84 (m, 3H), 7.84−7.78 (m, 4H), 7.59
(ddd, J = 7.9, 6.8, 1.2 Hz, 1H), 7.28 (d, J = 0.8 Hz, 1H), 6.92 (s, 1H),
2.67 (s, 3H), 2.41 (s, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
198.1, 160.5, 155.7, 154.8, 150.5, 146.0, 139.2, 138.8, 136.2, 134.5,
131.2, 130.0, 129.6, 129.6, 128.6, 128.0, 127.5, 127.3, 127.1, 124.9,
123.5, 26.9, 21.6 ppm. HRMS (ESI+): m/z calcd for C27H21N2O2 (M
+ H)+, 405.1598; found, 405.1592.
Accession Codes
CCDC 2010488, 2010491, and 2011442 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
General Method for One-Pot Dual Metal Ruthenium/
Palladium-Catalyzed C−H Arylation. A mixture of the azine
substrates 1−3 (0.50 mmol), aryl bromide 4 (0.50 mmol), [Ru(p-
3149
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J. Org. Chem. 2021, 86, 3138−3151

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Article
(14) Afewerki, S.; Córdova, A. Combinations of Aminocatalysts and
Metal Catalysts: A Powerful Cooperative Approach in Selective
Organic Synthesis. Chem. Rev. 2016, 116, 13512−13570.
(15) Pye, D. R.; Mankad, N. P. Bimetallic catalysis for C−C and C−
X coupling reactions. Chem. Sci. 2017, 8, 1705−1718.
AUTHOR INFORMATION
Corresponding Author
Helena Brodnik − Department of Organic Chemistry, Faculty
of Chemistry and Chemical Technology, University of
Ljubljana, 1000 Ljubljana, Slovenia; orcid.org/0000-
0002-0099-2236; Email: helena.brodnik@fkkt.uni-lj.si
■
(16) Trost, B. M.; Machacek, M. R. An efficient one-pot enantio-
and diastereoselective synthesis of heterocycles. Angew. Chem., Int. Ed.
2002, 41, 4693−4697.
Authors
(17) Ko, S.; Kang, B.; Chang, S. Cooperative Catalysis by Ru and Pd
for the Direct Coupling of a Chelating Aldehyde with Iodoarenes or
Organostannanes. Angew. Chem., Int. Ed. 2005, 44, 455−457.
(18) Ackermann, L.; Althammer, A. One-Pot 2-Aryl/Vinylindole
Synthesis Consisting of a Ruthenium-Catalyzed Hydroamination and
a Palladium-Catalyzed Heck Reaction Using 2-Chloroaniline. Synlett
2006, 2006, 3125−3129.
(19) Walker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.;
Anderson, E. A. Palladium- and Ruthenium-Catalyzed Cycloisomeri-
zation of Enynamides and Enynhydrazides: A Rapid Approach to
Diverse Azacyclic Frameworks. Angew. Chem., Int. Ed. 2013, 52,
9139−9143.
(20) Sustac Roman, D.; Poiret, V.; Pelletier, G.; Charette, A. B.
Direct Arylation of Imidazo[1,5-a]azines Through Ruthenium and
Palladium Catalysis. Eur. J. Org. Chem. 2015, 2015, 67−71.
(21) Mostafa, M. A. B.; Grafton, M. W.; Wilson, C.; Sutherland, A. A
one-pot, three-step process for the diastereoselective synthesis of
aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and
ruthenium(II)-catalysis. Org. Biomol. Chem. 2016, 14, 3284−3297.
(22) Yamamoto, K.; Qureshi, Z.; Tsoung, J.; Pisella, G.; Lautens, M.
Combining Ru-Catalyzed C−H Functionalization with Pd-Catalyzed
Asymmetric Allylic Alkylation: Synthesis of 3-Allyl-3-aryl Oxindole
Derivatives from Aryl α-Diazoamides. Org. Lett. 2016, 18, 4954−
4957.
Hamad H. Al Mamari − Department of Chemistry, College of
Science, Sultan Qaboos University, 123 Muscat, Oman
̌
̌
Uros Groselj − Department of Organic Chemistry, Faculty of
Chemistry and Chemical Technology, University of Ljubljana,
1000 Ljubljana, Slovenia
Franc Pozgan − Department of Organic Chemistry, Faculty of
̌
Chemistry and Chemical Technology, University of Ljubljana,
1000 Ljubljana, Slovenia; orcid.org/0000-0001-6040-
294X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01983
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Dedicated to Prof. Pierre H. Dixneuf for his outstanding
contribution to organometallic chemistry and ruthenium
■
̌
̌
̌
catalysis. Special thanks go to Masa Kastner, Tina Pecaric
̌
Strnad, and Ursa Rozman for laboratory support. We thank the
Slovenian Research Agency for financial support through grant
P1-0179. We also acknowledge the Centre of Excellence EN-
FIST.
(23) Manick, A.-D.; Berhal, F.; Prestat, G. Development of a One-
Pot Four C−C Bond-Forming Sequence Based on Palladium/
Ruthenium Tandem Catalysis. Org. Lett. 2018, 20, 194−197.
̌
̌
̌
̌
(24) Stefane, B.; Groselj, U.; Svete, J.; Pozgan, F.; Kocar, D.;
Brodnik, H. The Influence of the Quinoline Moiety on Direct Pd-
Catalyzed Arylation of Five-Membered Heterocycles. Eur. J. Org.
Chem. 2019, 2019, 432−441.
REFERENCES
■
(1) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Cooperative multi-catalyst
systems for one-pot organic transformations. Chem. Soc. Rev. 2004, 33,
302−312.
̌
̌
(25) Brodnik, H.; Pozgan, F.; Stefane, B. Synthesis of 8-heteroaryl
nitroxoline analogues via one-pot sequential Pd-catalyzed coupling
reactions. Org. Biomol. Chem. 2016, 14, 1969−1981.
(2) Batey, R. A. Domino Reactions in Organic Synthesis. J. Am.
Chem. Soc. 2007, 129, 7476−7476.
́
̌
̌
́
́
(26) Sosic, I.; Mitrovic, A.; Curic, H.; Knez, D.; Brodnik, H.; Stefane,
B.; Kos, J.; Gobec, S. Cathepsin B inhibitors: Further exploration of
the nitroxoline core. Bioorg. Med. Chem. Lett. 2018, 28, 1239−1247.
(27) Laroche, J.; Beydoun, K.; Guerchais, V.; Doucet, H. Direct
heteroarylation of 5-bromothiophen-2-ylpyridine and of 8-bromoqui-
nolineviapalladium-catalysed C−H bond activation: simpler access to
heteroarylated nitrogen-based derivatives. Catal. Sci. Technol. 2013, 3,
2072−2080.
(3) Hall, N. Chemists Clean Up Synthesis With One-Pot Reactions.
Science 1994, 266, 32−34.
(4) Bruggink, A.; Schoevaart, R.; Kieboom, T. Concepts of Nature in
Organic Synthesis: Cascade Catalysis and Multistep Conversions in
Concert. Org. Process Res. Dev. 2003, 7, 622−640.
(5) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Concurrent Tandem Catalysis. Chem. Rev. 2005, 105, 1001−1020.
(6) Tietze, L. F.; Brasche, G.; Gericke, K. In Domino Reactions in
Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinhiem, 2006.
(28) Bheeter, C. B.; Chen, L.; Soulé, J.-F.; Doucet, H.
Regioselectivity in palladium-catalysed direct arylation of 5-membered
ring heteroaromatics. Catal. Sci. Technol. 2016, 6, 2005−2049.
(29) Ackermann, L. Carboxylate-Assisted Transition-Metal-Cata-
lyzed C−H Bond Functionalizations: Mechanism and Scope. Chem.
Rev. 2011, 111, 1315−1345.
(7) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade
Reactions in Total Synthesis. Angew. Chem., Int. Ed. 2006, 45, 7134−
7186.
(8) Behr, A.; Vorholt, A. J.; Ostrowski, K. A.; Seidensticker, T.
Towards resource efficient chemistry: tandem reactions with renew-
ables. Green Chem. 2014, 16, 982−1006.
̌
̌
(30) Stefane, B.; Brodnik, H.; Groselj, U.; Kuzman, P.; Svete, J.;
̌
Pozgan, F. Quinazoline-Directed C−H Bond Functionalization
Catalyzed by Ruthenium(II) Carboxylate − Construction of
Polyconjugated Aryl-Heteroaryl Systems. Eur. J. Org. Chem. 2017,
2017, 1855−1864.
(9) Hayashi, Y. Pot economy and one-pot synthesis. Chem. Sci. 2016,
7, 866−880.
(10) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, U.K., 1998.
̌
̌
(31) Drev, M.; Groselj, U.; Ledinek, B.; Perdih, F.; Svete, J.; Stefane,
̌
B.; Pozgan, F. Microwave-Promoted ortho-C−H Bond (Hetero)-
(11) Muller, T. J. J. In Metal Catalyzed Cascade Reactions; Topics in
̈
arylation of Arylpyrimidines in Water Catalyzed by Ruthenium(II)−
Carboxylate. ChemCatChem 2018, 10, 3824−3832.
Organometallic Chemistry; Springer-Verlag: Berlin Heidelberg, 2006.
(12) Allen, A. E.; Macmillan, D. W. C. Synergistic catalysis: A
powerful synthetic strategy for new reaction development. Chem. Sci.
2012, 3, 633−658.
̌
̌
(32) Drev, M.; Groselj, U.; Ledinek, B.; Perdih, F.; Svete, J.; Stefane,
̌
B.; Pozgan, F. Ruthenium(II)-Catalyzed Microwave-Promoted Multi-
ple C-H Activation in Synthesis of Hexa(heteroaryl)benzenes in
(13) Du, Z.; Shao, Z. Combining transition metal catalysis and
organocatalysis − an update. Chem. Soc. Rev. 2013, 42, 1337−1378.
Water. Org. Lett. 2018, 20, 5268−5273.
3150
https://dx.doi.org/10.1021/acs.joc.0c01983
J. Org. Chem. 2021, 86, 3138−3151

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(33) Rajkumar, S.; Karthik, S.; Gandhi, T. Ru(II)-Catalyzed β-
Carboline Directed C−H Arylation and Isolation of Its Cyclo-
ruthenated Intermediates. J. Org. Chem. 2015, 80, 5532−5545.
(34) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Cross-Coupling of
Heteroarenes by C−H Functionalization: Recent Progress towards
Direct Arylation and Heteroarylation Reactions Involving Hetero-
arenes Containing One Heteroatom. Adv. Synth. Catal. 2014, 356,
17−117.
(35) Cantat, T.; Génin, E.; Giroud, C.; Meyer, G.; Jutand, A.
Structural and kinetic effects of chloride ions in the palladium-
catalyzed allylic substitutions. J. Organomet. Chem. 2003, 687, 365−
376.
(36) CrysAlis PRO; Agilent Technologies UK Ltd.: Yarnton,
Oxfordshire, England, 2011.
(37) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. OLEX2: a complete structure solution, refinement
and analysis program. J. Appl. Crystallogr. 2009, 42, 339−341.
(38) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr.,
Sect. A: Found. Crystallogr. 2008, 64, 112−122.
(39) Sheldrick, G. M. Crystal structure refinement with SHELXL.
Acta Crystallogr., Sect. A: Found. Adv. 2015, 71, 3−8.
(40) Sheldrick, G. M. Crystal structure refinement with SHELXL.
Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3−8.
(41) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.;
Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury:
visualization and analysis of crystal structures. J. Appl. Crystallogr.
2006, 39, 453−457.
(42) Spek, A. L. Single-crystal structure validation with the program
PLATON. J. Appl. Crystallogr. 2003, 36, 7−13.
(43) Maheswari, C. U.; Kumar, G. S.; Venkateshwar, M.; Kumar, R.
A.; Kantam, M. L.; Reddy, K. R. Highly Efficient One-Pot Synthesis of
2-Substituted Quinazolines and 4H-Benzo[d][1,3]oxazines via Cross
Dehydrogenative Coupling using Sodium Hypochlorite. Adv. Synth.
Catal. 2010, 352, 341−346.
(44) Li, B.; Roisnel, T.; Darcel, C.; Dixneuf, P. H. Cyclometallation
of arylimines and nitrogen-containing heterocycles via room-temper-
ature C−H bond activation with arene ruthenium(II) acetate
complexes. Dalton Trans. 2012, 41, 10934−10937.
3151
https://dx.doi.org/10.1021/acs.joc.0c01983
J. Org. Chem. 2021, 86, 3138−3151