Synthesis of 8-heteroaryl nitroxoline analogues via one-pot sequential Pd-catalyzed coupling reactions

Article abstract of DOI:10.1039/c5ob02364e

A series of 8-heteroaryl substituted quinolines were prepared, either by direct C-H arylation of five-membered heteroarenes, or Pd-catalyzed coupling of organoboron reagents with bromoquinolines. The use of (benzo)thiophenyl or (benzo)furanyl boron coupling partners allowed further C-H functionalization on the five-membered heteroaryl ring with aryl bromides in one flask to access a variety of polyconjugated molecular architectures. The developed methodology represents a simple approach towards 8-arylated analogues of the biologically interesting nitroxoline core.

Full text of DOI:10.1039/c5ob02364e

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Synthesis of 8-heteroaryl nitroxoline analogues
via one-pot sequential Pd-catalyzed coupling
reactions†
Cite this: DOI: 10.1039/c5ob02364e
Helena Brodnik, Franc Požgan and Bogdan Štefane*
A series of 8-heteroaryl substituted quinolines were prepared, either by direct C–H arylation of five-mem-
bered heteroarenes, or Pd-catalyzed coupling of organoboron reagents with bromoquinolines. The use
of (benzo)thiophenyl or (benzo)furanyl boron coupling partners allowed further C–H functionalization on
the five-membered heteroaryl ring with aryl bromides in one flask to access a variety of polyconjugated
molecular architectures. The developed methodology represents a simple approach towards 8-arylated
analogues of the biologically interesting nitroxoline core.
Received 17th November 2015,
Accepted 4th December 2015
DOI: 10.1039/c5ob02364e
www.rsc.org/obc
5-methoxy-8-chloroquinoline coupled with phenylboronic acid
in the presence of Ni(C) catalyst under relatively harsh reaction
Introduction
8-Arylquinoline is one of the pharmaceutically important conditions.15 An example of Negishi cross-coupling of
scaffolds present in many molecules which have shown a 8-chloroquinoline catalysed by
a Ni(II)/diethyl phosphite
variety of biological activity,1 and has also been designed as a system16 and regioselective functionalization of a quinoline
key structural element in materials science.2 Recently, we have moiety via magnesiation17 was described by Knochel and
described the synthesis of new potential cathepsin B inhibitors co-workers. Macdonald et al. described an elegant synthetic
based on 1,3,5-triazin-2(1H)-one3 and nitroxoline (8-hydroxy-5- approach to phosphodiesterase type 4 photoaffinity probe by
nitroquinoline)4 scaffolds. To further explore the structure– applying a cross-coupling step between 8-bromo-6-quinolinic
activity relationship an efficient synthetic approach to obtain a acid and 3-aminobenzeneboronic acid.18
variety of 8-(hetero)arylquinoline derivatives was required.
Therefore, we focused on metal-catalyzed arylations, which
have found a wide application in the synthesis of bi(hetero)-
Results and discussion
aryl systems. Indeed, the quinoline moiety has often been deri-
vatized via Pd-,5 Ni-,6 Rh-,7 Cu-,8 and Ag-catalysed9 reactions
From the retrosynthetic point of view, 8-heteroarylquinoline
producing mostly 2- and 4-arylated products. More recently,
derivatives could simply be prepared by metal-catalyzed hetero-
two methods for catalytic arylation of quinolines at the 8-posi-
arylation via C–H activation of furans, thiophenes, pyrroles,
tion have been described,10,11 of which direct functionalization
oxazoles, thiazoles, and their benzo derivatives with 8-halo-
with a Rh(NHC)-based catalyst11 appeared as the most attrac-
quinolines. In most cases, intramolecular arylations or inter-
tive. In the course of development of cross-coupling synthetic
molecular C5-arylations of C2-substituted five membered
methodologies some individual examples of quinoline aryla-
heterocycles have been extensively studied.19 However, the
tion at the 8-position have also appeared in the literature. For
direct arylation of some fundamental heterocycles, such as
example, the Suzuki reaction of 5-bromoindanone and (quino-
furan, thiophene, and pyrrole to prepare their 2-arylated
line-8-yl)boronic acid gave the corresponding cross-coupling
derivatives was found to be problematic.20 Guerchais, Doucet,
product in good yield.12 Quinoline-8-yl triflate was used as a
and co-workers documented palladium-catalyzed direct hetero-
coupling partner in the decarboxylative arylation with potass-
arylation of 8-bromoquinoline in moderate to good yields.21
ium arylcarboxylates13 and arylation with potassium (hetero)-
Being aware of their successful examples we set out our syn-
aryltrifluoroborates14 catalyzed by Pd catalysts, while
thetic approach towards 8-heteroarylquinoline derivatives via
direct Pd-catalysed arylation of furan, thiophene, 1-methyl-1H-
pyrrole, and their benzo derivatives. The starting material,
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot
8-bromo-5-nitroquinoline (2), was prepared from commercially
113, SI-1000 Ljubljana, Slovenia. E-mail: bogdan.stefane@fkkt.uni-lj.si
available 8-bromoquinoline (1). The most appropriate nitration
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob02364e
reagent for 8-bromoquinoline was found to be an excess of
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KNO3 in concentrated sulphuric acid, wherein the reaction line (1) progressed up to 73% conversion in 24 h, it was
time played a crucial role in obtaining a good yield (86%) of accompanied by the pronounced dimerization of 8-bromo-
the product 2.
quinoline. Consequently, we were able to isolate only 8% of the
Having the starting materials in hand, we initiated the pure product 4e. Slightly better but still unsatisfactory results
coupling chemistry with the model reaction of 8-bromoquino- were obtained with benzo[b]thiophene (Table 1, entry 6). It
line (1) with furan. After thorough screening of different cata- should be mentioned that the optimized reaction conditions
lytic systems and reaction conditions22 we found Pd(OAc)2 failed for the coupling of 8-bromo-5-nitroquinoline (2) either
(5 mol%) in combination with SPhos (10 mol%) and K3PO4 as with benzo[b]furan or benzo[b]thiophene resulting in a rather
the base in NMP at 150 °C as optimal reaction conditions. complex reaction mixture. For comparison, we also found that
When 5 equivalents of furan were used, we achieved a com- 8-bromoquinoline is much less reactive than the 2- or 3-bromo
plete conversion of 8-bromoquinoline yielding 4a (Table 1) analogues, since they can be successfully coupled with furan
together with a significant amount of side product 5a (ratio at lower temperature (130 °C) using Pd(OAc)2 (1 mol%) and
4a : 5a = 1 : 2.4) produced by dimerization of 8-bromoquino- PPh3 as a ligand.
line. However, we were able to reduce the dimerization process
Since we found some limitations in the direct arylation
of 8-bromoquinoline under the given reaction conditions only approach with unsubstituted five-membered heteroarenes and
by applying a large excess of furan. When furan was used as a being aware that it would be difficult to access targeted C3-qui-
co-solvent (NMP-furan in a ratio of 1 : 1 (v/v)), the complete nolinyl heteroarenes we turned to the coupling chemistry with
conversion of 8-bromoquinoline was achieved in 24 h at the model reaction of 8-bromoquinoline (1) with (furan-3-yl)-
150 °C and the ratio of products 4a : 5a (10 : 1) changed in boronic acid testing different catalytic systems and reaction
favour of the desired product 4a. Under the optimized reaction conditions.22 The reaction was found to be rather sluggish at
conditions both bromoquinolines 1 and 2 can be successfully temperatures below 80 °C in toluene in the presence of
coupled with furan, thiophene, and 1-methyl-1H-pyrrole only if Pd(PPh3)4 or Pd(OAc)2 complexes. Thus, a set of different Pd-cat-
they are used in a large excess (Table 1). On the other hand, alysts, most of which were generated in situ from a Pd-source
the method, using a large excess of heteroarene, was found to and triphenylphosphine ligand, were tested in several solvents
be impractical for benzo[b]furan (3e) and benzo[b]thiophene at 100 °C. Most of the commonly used Pd-precatalysts more or
(3f); for this reason only 5 equivalents of 3e and 3f were used. less successfully coupled 8-bromoquinoline with (furan-3-yl)-
Even though, arylation of benzo[b]furan with 8-bromoquino- boronic acid. However, the catalyst system Pd(OAc)2/PPh3,
K2CO3 in the mixture of 1,4-dioxane/water 4 : 1 (v/v) was
chosen to be the most practical. Moreover, the addition of
water to the reaction mixture could also contribute to
sufficiently solubilize the base.
In continuation, the scope of Suzuki–Miyaura cross-coup-
ling of bromoquinolines 1 and 2 with different heteroarylboro-
nic acids 6 was investigated by applying optimized reaction
conditions. The reactions with both substrates 1 and 2 were
complete in 3–24 h providing the corresponding 8-heteroaryl-
quinoline coupling products 4 in good yields (Table 2). Since
microwave (MW) conditions have been shown to be beneficial
in some examples of Suzuki–Miyaura reactions,23 we ran
selected reactions under microwave irradiation at 100 °C in a
1,4-dioxane/water (4 : 1) solvent system for 3 h. However, our
results show that there is no beneficial effect of using MW con-
ditions, and in some cases even lower yields of the isolated
products 4 were obtained (Table 2, yields in brackets).
Table 1 Synthesis of the 8-heteroarylquinolines via Pd-catalyzed direct
arylation
Conversion %
Entry R1
Heteroarene 3
(4 : 5)c
4; (yield)d
Suzuki–Miyaura cross-coupling of 8-bromoquinolines 1 and
2 with heteroarylboronic acids 6a–g allowed the introduction
of a variety of pyrrolyl, furanyl, thiophenyl, and their benzo
analogues at the 8-position of the quinoline nucleus in good
to excellent yields. In the case of using N-Boc-pyrrole-2-boronic
acid (Table 2, entries 4 and 11) as the coupling partner the Boc
group was removed in the course of the reaction, as also
noticed by other researchers.24
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
NO2
NO2
NO2
NO2
Furan (3a)
100 (10 : 1)a
100 (10 : 1)a
100 (6 : 1)a
4a (48)
4b (59)
4c (39)
4d (61)
4e (8)
4f (28)
4g (44)
4h (53)
4i (35)
4j (57)
Thiophene (3b)
2-Methylthiophene (3c)
1-Methyl-1H-pyrrole (3d) 100 (10 : 1)a
Benzo[b]furan (3e)
Benzo[b]thiophene (3f)
Furan (3a)
Thiophene (3b)
2-Methylthiophene (3c)
73 (1 : 2.7)b
100 (2 : 1)b
100a
100a
100 (5 : 1)a
1-Methyl-1H-pyrrole (3d) 100
When 1 was coupled with (thiophene-3-yl)boronic acid (6c)
in the presence of Pd(OAc)2 and PPh3 at temperatures higher
than 100 °C, beside 4l we also isolated a minor quantity (2%)
of the side product 4l′, 8,8′-(thiophene-2,3-diyl)diquinoline,
Conditions: a Pd(OAc)2 (5 mol%), SPhos (10 mol%), K3PO4 (1.0 mmol),
8-bromoquinoline 1 or 2 (0.5 mmol), heteroarene (1.0 mL), NMP
(1.0 mL). b Heteroarene (2.5 mmol). c Ratio determined by 1H NMR of
the crude reaction mixture. d isolated yields are given.
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Table 2 Suzuki–Miyaura cross-coupling of 1 and 2 with heteroaryl-
boronic acids 6
Scheme 1 Coupling reaction between
1
and 6c at elevated
temperature.
Entry
1
R1
H
Boronic acid 6
4; yielda (MW-yield), %
4c; 70 (42)
This result suggested that a one-pot Suzuki–Miyaura coup-
ling reaction followed by C–H arylation of an already installed
heteroarene moiety could be feasible. The development of
multistep synthetic sequences in a single flask, such as
tandem, cascade, or sequential reactions is highly desirable in
the chemistry community. There are a number of advantages
of such processes, such as reduction of cost, time, and waste.
Additionally, such a methodology enables the production of
large molecular diversity and the introduction of a wide degree
of complexity in a single transformation.25 There are several
examples where the Suzuki–Miyaura coupling reaction was
combined in a one-pot procedure, for example with C–H cross-
coupling reaction,26 Heck coupling,27 isoxazole fragmenta-
tion,28 Michael addition,29 aza-Michael reaction,30 and con-
densation reaction.31
Investigation towards one-pot sequential procedure was
initiated with the Suzuki–Miyaura cross-coupling between
8-bromoquinoline (1) and (furan-3-yl)boronic acid (6b)
employing the catalyst Pd(OAc)2–PPh3, and a 1,4-dioxane/H2O
solvent system. The subsequent C–H arylation was then
carried out by simply adding 4-bromoacetophenone after the
completion of the Suzuki coupling. In order to obtain high
conversions, additional 5 mol% of the catalyst (Pd(OAc)2)
without the additional loading of the ligand (PPh3) was
required. The resulting reaction mixture was further stirred for
24 h while raising the temperature to 120 °C. Pleasingly, the
expected arylated product 7a was obtained in a high 80% iso-
lated yield (Scheme 2). A 1,4-dioxane–H2O, 4/1 (v/v) solvent
system was found to be superior among the tested solvents
(toluene, 1,4-dioxane, NMP, 2-propanol, and water). Even
though 2-propanol32 showed promising results in the Suzuki–
Miyaura cross-coupling reaction, the subsequent C–H acti-
vation step was almost completely inhibited in this solvent.
The Suzuki–Miyaura cross-coupling products of 1 and 2 with
commercially available heteroarylboronic acids 6b, 6c, 6e, 6f,
and 6g allowed efficient subsequent C–H arylation of (benzo)-
furan, (benzo)thiophene, and pyrrole ring using different aryl-
bromides as electrophiles, mostly affording monoarylated final
products 7 (Scheme 2).
2
3
H
H
4k; 85 (63)
4l; 70 (63)
4
5
H
H
4m; 57 (20)b
4d; 96
6
7
H
H
4e; 97 (33)
4f; 92 (29)
8
9
NO2
NO2
4i; 74 (31)
4n; 85(45)
10
NO2
4o; 90 (65)
11
12
NO2
NO2
4p; 62b
4j; 99
13
14
NO2
NO2
4q; 79 (30)
4r; 69 (32)
a Isolated yields are reported. b The Boc group was removed during the
reaction.
Detailed structural analysis of the monoarylated products
7a–h using X-ray analysis and 2D NMR techniques confirmed
the formation of C2 arylated products that is in consistency
with the literature data published to a large extent by Doucet
and co-workers on C3 substituted furans,33 pyrroles,34 and
thiophenes.35 The C–H arylation of 8-(thiophene-2-yl)- and
8-(N-methylpyrrol-2-yl)quinolines 4b and 4d (Scheme 2, products
arising from the arylation of the thiophene ring of the already
formed Suzuki coupling product 4l with 8-bromoquinoline
(Scheme 1).
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we speculate that the nitro group in the case of the C-5 arylated
product 7u may also have influence on the reactivity of the C-5
position, since in the analogue product 7s (lacking nitro func-
tionality) C-3 arylation occurred. The examination of the set of
aryl bromides as the coupling partners revealed that the aryl
halides bearing an electron-accepting group reacted relatively
well with the 8-heteroarylquinoline derivatives under the given
reaction conditions. 4-Bromoanisole, bearing an electron-
donating group, was found to be less reactive. However, by
simply elevating the reaction temperature from 120 °C to
150 °C we were able to isolate the desired product 7l in an 80%
yield (Scheme 2).
Furthermore, we were able to accomplish a three-step one-
pot transformation, which included the Suzuki–Miyaura cross-
coupling reaction of 2 and 6b followed by two C–H arylations
of the furan-3-yl moiety of the formed intermediate 4n using
two different aryl bromides. The corresponding product 8 was
isolated in a reasonable 45% yield (Scheme 3).
Finally, we examined the possibility of combining the
Suzuki–Miyaura cross-coupling reaction, direct C–H arylation
reaction, and hydrogenation reaction in a one-pot synthetic
procedure. The Suzuki–Miyaura cross-coupling reaction of
8-bromo-5-nitroquinoline (2) and benzo[b]furan-2-yl boronic
acid (6f) delivered product 4q which was arylated with
4-bromonitrobenzene and the crude reaction mixture was then
exposed to the atmosphere (1 atm) of hydrogen at room temp-
erature for 24 h. The final product 9 (Scheme 4) was isolated in
good (70%) overall yield.
Scheme 2 One-pot synthesis of quinoline derivatives 7 by sequential
Suzuki–Miyaura cross-coupling/C–H arylation reaction.
7q–t) predominantly occurred at the C3 position rather than at
C5. In case of arylation of nitro analogue 4j with 4-bromoaceto-
phenone the C5 site selectivity was prevalent (Scheme 2,
example 7u). To clarify the synthesis of 7t, the Suzuki–Miyaura
reaction between 8-bromoquinoline (1) and potassium thio-
phene-2-yl trifluoroborate was achieved in 1,4-dioxane at 80 °C
in the presence of a catalyst, which was synthesized form
2-aminobiphenyl, Pd(OAc)2 and SPhos (catalyst A).32 However,
our results indicate that the catalyst A is not successful in per-
forming the C–H arylation synthetic step, consequently, the
arylation step was then performed with loading of Pd(OAc)2
(5 mol%), PPh3 (10 mol%), and K2CO3 and heating the reac-
tion mixture at 120 °C for 24 h. The final product 7t was iso-
lated in a modest 30% yield.
According to the 1H NMR spectrum of the crude reaction
mixtures only traces of diarylated products were detected.
However, in four particular cases we were able to isolate the
diarylated products 7ca, 7ea, 7qa and 7ra in pure form
(Scheme 2). To minimize the formation of the diarylated pro-
ducts 0.80 equivalents of the aryl bromides were used in the
arylation step assuming the complete conversion of the
Suzuki–Miyaura cross-coupling reaction.
Scheme 3 One-pot synthesis of polyarylated furan.
According to the results of regioselectivity in the above-
mentioned examples one could suggest the directing influence
of the quinoline nitrogen in C–H activations,36 which is rather
small due to a six-membered palladacyclic transition state and
can be, in particular examples (Scheme 2, examples of mono-
arylated product 7u and diarylated products 7ca and 7ea), over-
written by the grater reactivity of the C-5 position. Additionally,
Scheme 4 One-pot Suzuki–Miyaura cross-coupling/arylation/hydro-
genation reaction sequence.
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anhydrous Na2SO4, filtered and evaporated under reduced
pressure to obtain 2.42 g (86%) of pure product 2.
Conclusions
In summary, an original two-step single-flask palladium-
Light yellow solid; Rf (light petroleum/EtOAc = 5/3) 0.48.
catalyzed Suzuki–Miyaura cross-coupling/direct C–H arylation FT-IR (ATR, neat): 3087, 1594, 1511, 1487, 1393, 1323, 1286,
sequence was developed starting from readily available 921, 841, 806, 776 cm−1 1H NMR (500 MHz, CDCl3): δ 9.17
.
8-bromo- and 8-bromo-5-nitroquinoline. The method enables (dd, J = 4.0, 1.5 Hz, 1H), 9.07 (dd, J = 9.0, 1.5 Hz, 1H), 8.26 (d,
a straightforward derivatization of primarily formed heteroaryl J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 9.0,
Suzuki–Miyaura cross-coupling products with aryl bromides as 4.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 152.2, 145.0, 144.9,
proelectrophiles. In addition, we have demonstrated that our 133.3, 132.6, 131.4, 124.7, 122.1. HRMS (ESI−): m/z calcd for
single-flask multicoupling approach successfully allowed the C9H6BrN2O2 (M + H)+: 252.9607; found: 252.9609. Elemental
preparation of a 2,5-non-symmetrically diarylated furanyl quino- analysis calcd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07;
line product 8 by implementing two consecutive arylation found: C, 42.76; H, 1.83; N, 10.90.
steps. This sequential synthetic approach supplies a variety of
hetero(aryl) functionalized quinolines being potential inhibi-
tors of the cathepsin family of enzymes. Furthermore, the
photophysical and electrochemical properties of some syn-
General procedure for the synthesis of 8-heteroarylquinolines
via Pd-catalyzed direct arylation (4a–j)
thesized products are under investigation.
The corresponding quinoline (1, 2) (0.50 mmol), Pd(OAc)2
(5.6 mg, 0.025 mmol), SPhos (20.5 mg, 0.050 mmol) and
K3PO4 (212 mg, 1.00 mmol) were dissolved in NMP. In the case
of direct arylation of furan (3a), thiophene (3b), 2-methyl-
thiophene (3c) and 1-methyl-1H-pyrrole (3d) the latter were
added as a co-solvent (1 mL and 1 mL of NMP). In the case of
Experimental
General information
Unless specified, commercial-grade reagents were used direct arylation of benzo[b]furan (3e) and benzo[b]thiophene
without further purification. Reactions were monitored by (3f) 5 equiv. (2.50 mmol) and 2 mL of NMP were added. The
analytical thin-layer chromatography (TLC) or reverse-phase reaction mixture was stirred in a sealed glass tube at 150 °C for
HPLC. Visualization of the developed TLC chromatogram was 24 h under an inert atmosphere. The mixture was allowed to
performed by UV absorbance or aqueous potassium per- cool to r.t. to which water was added (3 mL) and the product
manganate. Flash chromatography was performed on 230–400- was extracted into dichloromethane (2 × 3 mL). The combined
mesh silica gel with the indicated solvent system. Yields refer organic layers were dried (Na2SO4) and filtered, and the
to chromatographically and spectroscopically (1H and 13C solvent was evaporated under reduced pressure. The crude
NMR) homogeneous materials. Melting points are uncorrected. product was purified by radial chromatography to yield pure
Infra-red spectra were recorded on a FT-IR spectrometer product 4.
and are reported in reciprocal centimeters (cm−1). Routine
8-(Furan-2-yl)quinoline (4a). Radial chromatography on
nuclear magnetic resonance spectra were recorded either on a silica gel (eluting with petroleum ether/EtOAc; 20/1). Colorless
Bruker Avance DPX 300 or Avance III 500 MHz spectrometer. oil (47 mg, 48%); Rf (light petroleum/EtOAc = 10/1) 0.51. FT-IR
1
Chemical shifts for H NMR spectra are recorded in parts per (ATR, neat): 3060, 1582, 1501, 1015, 818, 790, 736 cm−1
.
1H
million (ppm) from tetramethylsilane as an internal standard. NMR (500 MHz, CDCl3): δ 9.00 (dd, J = 4.0, 2.0 Hz, 1H), 8.24
Data are reported as follows: chemical shift, multiplicity, (s = (dd, J = 7.5, 1.5 Hz, 1H), 8.16 (dd, J = 8.5, 2.0 Hz, 1H), 7.81 (d,
singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sext = J = 3.5 Hz, 1H), 7.71 (dd, J = 8.0, 1.5 Hz, 1H), 7.60–7.75 (m,
sextet, sept = septet, m = multiplet, and br = broad), number of 2H), 7.43 (dd, J = 8.0, 4.0 Hz, 1H), 6.61 (dd, J = 3.5, 2.0 Hz, 1H).
equivalent nuclei (by integration), coupling constants (J) quoted 13C NMR (125 MHz, CDCl3): δ 151.3, 149.9, 144.3, 141.9, 136.4,
in Hertz to the nearest 0.25 Hz. Chemical shifts for the 13C 128.9, 128.6, 127.0, 126.4, 126.0, 121.0, 113.0, 112.1. HRMS
NMR spectra are recorded in parts per million from tetramethyl- (ESI+): m/z calcd for C13H10NO (M + H)+: 196.0757; found:
silane using the central peak of the solvent resonance as an 196.0756.
internal standard. All spectra were obtained with complete
8-(Thiophen-2-yl)quinoline (4b). Radial chromatography on
proton decoupling. High-resolution mass spectra were recorded silica gel (eluting with petroleum ether/EtOAc; 50/1). Light
on an Agilent 6224 Accurate Mass TOF LC/MS instrument by yellow oil (62 mg, 59%); Rf (light petroleum/EtOAc = 10/1) 0.44.
electrospray ionization operating at a resolution of 15 000 full FT-IR (ATR, neat): 3065, 1494, 1311, 937, 820, 787, 694 cm−1
widths at half height.
.
1H NMR (500 MHz, CDCl3): δ 9.01 (dd, J = 4.0, 2.0 Hz, 1H),
8-Bromo-5-nitroquinoline (2). 8-Bromoquinoline (1) (2.3 g, 8.16 (dd, J = 8.0, 2.0 Hz, 1H), 8.06 (dd, J = 7.5, 1.5 Hz, 1H), 7.79
11.2 mmol) was slowly added to a mixture of H2SO4 (7 mL, (dd, J = 3.5, 1.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 (dd,
98%) and KNO3 (4.5 g, 44.6 mmol) at 0 °C. The reaction J = 8.0, 7.5 Hz, 1H), 7.48 (dd, J = 5.0, 1.0 Hz, 1H), 7.43 (dd, J =
mixture was allowed to warm to room temperature at which it 8.0, 4.0 Hz, 1H), 7.17 (dd, J = 5.0, 3.5 Hz, 1H). 13C NMR
was stirred for 2 h. The mixture was basified with a saturated (125 MHz, CDCl3): δ 149.5, 144.6, 139.7, 136.3, 133.0, 128.7,
solution of Na2CO3 to pH = 9 and extracted with ethyl acetate 128.0, 127.9, 127.1, 126.7, 126.6, 126.4, 121.2. HRMS (ESI+):
(3 × 20 mL). The combined organic layers were dried over m/z calcd for C13H10NS (M + H)+: 212.0528; found: 212.0528.
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8-(5-Methylthiophen-2-yl)quinoline (4c). Radial chromato- EtOAc = 10/1) 0.47. FT-IR (ATR, neat): 3117, 2920, 1499, 1322,
graphy on silica gel (eluting with petroleum ether/EtOAc; 20/1). 1183, 1025, 948, 811, 787, 738 cm−1 1H NMR (500 MHz,
.
Light green oil (44 mg, 39%); Rf (light petroleum/EtOAc = 10/1) CDCl3): δ 9.11 (dd, J = 9.0, 2.0 Hz, 1H), 9.07 (dd, J = 4.0, 2.0 Hz,
0.49. FT-IR (ATR, neat): 2914, 1496, 1474, 1046, 827, 794, 753, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.08 (d, J =
1
650 cm−1. H NMR (500 MHz, CDCl3): δ 9.00 (dd, J = 4.0, 2.0 3.5 Hz, 1H), 7.67–7.65 (m, 2H), 6.66 (dd, J = 3.5, 2.0 Hz, 1H).
Hz, 1H), 8.15 (dd, J = 8.5, 2.0 Hz, 1H), 8.01 (dd, J = 7.5, 1.5 Hz, 13C NMR (125 MHz, CDCl3): δ 150.5, 149.9, 143.9, 143.5, 143.1,
1H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.57 (d, J = 3.5 Hz, 1H), 134.0, 132.3, 125.1, 123.7, 123.2, 121.8, 117.4, 113.0. HRMS
7.55–7.52 (m, 1H), 7.42 (dd, J = 8.0, 4.0, 1H), 6.82 (dd, J = 3.5, (ESI+): m/z calcd for C13H9N2O3 (M + H)+: 241.0608; found:
1.0 Hz, 1H), 2.57 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 149.3, 241.0608.
144.6, 142.6, 137.3, 136.3, 133.4, 128.7, 127.4, 126.7, 126.6,
126.4, 124.9, 121.1, 15.3. HRMS (ESI+): m/z calcd for C14H12NS graphy on silica gel (eluting with petroleum ether/EtOAc; 25/1).
(M + H)+: 226.0685; found: 226.0684.
Yellow solid (68 mg, 53%); mp = 144–147 °C; Rf (light pet-
8-(1-Methyl-1H-pyrrol-2-yl)quinoline (4d). Radial chromato- roleum/EtOAc = 10/1) 0.35. FT-IR (ATR, neat): 3088, 1558, 1498,
graphy on silica gel (eluting with petroleum ether/EtOAc; 50/1). 1418, 1397, 1327, 1305, 902, 851, 812 cm−1 1H NMR
5-Nitro-8-(thiophen-2-yl)quinoline (4h). Radial chromato-
.
Colorless oil (63 mg, 61%); Rf (light petroleum/EtOAc = 5/3) (500 MHz, CDCl3): δ 9.15 (dd, J = 9.0, 1.5 Hz, 1H), 9.11 (dd, J =
0.46. FT-IR (ATR, neat): 3046, 2940, 1498, 1314, 958, 831, 4.0, 1.5 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.17, (d, J = 8.5 Hz,
1
706 cm−1. H NMR (500 MHz, CDCl3): δ 8.95 (dd, J = 4.0, 2.0 1H), 7.94 (d, J = 4.0 Hz, 1H), 7.69 (dd, J = 9.0, 4.0 Hz, 1H), 7.65
Hz, 1H), 8.18 (dd, J = 8.0, 2.0 Hz, 1H), 7.83 (dd, J = 8.0, 1.5 Hz, (d, J = 5.0, 1H), 7.22 (d, J = 5.0, 4.0 Hz, 1H). 13C NMR
1H), 7.73 (dd, J = 7.0, 1.5 Hz, 1H), 7.58–7.55 (m, 1H), 7.39 (dd, (125 MHz, CDCl3): δ 149.9, 143.8, 143.1, 139.9, 137.8, 132.4,
J = 8.0, 4.0 Hz, 1H), 6.84–6.83 (m, 1H), 6.32–6.29 (m, 2H), 3.47 131.9, 128.9, 126.9, 125.1, 124.8, 123.9, 122.0. HRMS (ESI+):
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 150.4, 147.0, 136.1, m/z calcd for C13H8N2O2S (M + H)+: 257.0385; found: 257.0387.
133.0, 132.2, 131.9, 128.5, 127.9, 126.1, 123.2, 120.9, 110.0,
107.7, 35.3. HRMS (ESI+): m/z calcd for C14H13N2 (M + H)+: chromatography on silica gel (eluting with petroleum ether/
209.1073; found: 209.1074. EtOAc; 20/1). Yellow solid (47 mg, 35%); mp = 162–164 °C; Rf
8-(Benzofuran-2-yl)quinoline (4e). Radial chromatography (light petroleum/EtOAc = 3/1) 0.46. FT-IR (ATR, neat): 2916,
on silica gel (eluting with petroleum ether/EtOAc; 20/1). Yellow 1497, 1469, 1442, 1393, 1356, 844, 803, 783 cm−1 1H NMR
8-(5-Methylthiophen-2-yl)-5-nitroquinoline
(4i). Radial
.
solid (9 mg, 8%); mp = 102–104 °C; Rf (light petroleum/EtOAc (500 MHz, CDCl3): δ 9.15 (dd, J = 8.9, 1.7 Hz, 1H), 9.08 (dd, J =
= 3/1) 0.46. FT-IR (ATR, neat): 3030, 1499, 1450, 1259, 1109, 4.1, 1.7 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz,
1
821, 792, 741 cm−1. H NMR (500 MHz, CDCl3): δ 9.07 (dd, J = 1H), 7.75 (d, J = 3.8, 1H), 7.67 (dd, J = 8.9, 4.1 Hz, 1H), 6.88 (d,
4.1, 1.8 Hz, 1H), 8.50 (dd, J = 7.4, 1.4 Hz, 1H), 8.30 (d, J = 0.9 J = 3.8 Hz, 1H), 2.60 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
Hz, 1H), 8.22 (dd, J = 8.2, 1.8 Hz, 1H), 7.81 (dd, J = 8.1, 1.4 Hz, 149.6, 147.2, 143.6, 142.4, 140.2, 135.3, 132.4, 129.2, 125.4,
1H), 7.70–7.64 (m, 2H) 7.57 (dd, J = 8.2, 0.9 Hz, 1H), 7.49 (dd, 125.3, 123.9, 123.8, 122.1, 15.4. HRMS (ESI+): m/z calcd for
J = 8.2, 4.1 Hz, 1H), 7.34–7.30 (m, 1H), 7.27–7.24 (m, 1H). 13C C14H11N2O2S (M + H)+: 271.0536; found: 271.0536. Elemental
NMR (125 MHz, CDCl3): δ 154.2, 153.0, 150.1, 144.9, 136.5, analysis calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36;
129.9, 128.6, 128.4, 128.2, 127.4, 126.3, 124.5, 122.7, 121.6, found: C, 62.15; H, 3.87; N, 10.37.
121.2, 110.9, 109.6. HRMS (ESI+): m/z calcd for C17H12NO (M +
8-(1-Methyl-1H-pyrrol-2-yl)-5-nitroquinoline
(4j). Radial
H)+: 246.0913; found: 246.0914. Elemental analysis calcd for chromatography on silica gel (eluting with petroleum ether/
C17H11NO: C, 83.25; H, 4.52; N, 5.71; found: C, 82.79; H, 4.33; EtOAc; 10/1). Orange solid (72 mg, 57%); mp = 119–120 °C; Rf
N, 5.62.
(light petroleum/EtOAc = 5/3) 0.51. FT-IR (ATR, neat): 3119,
1H NMR
8-(Benzo[b]thiophen-2-yl)quinoline (4f). Radial chromato- 1509, 1497, 1328, 1311, 846, 814, 793, 735 cm−1
.
graphy on silica gel (eluting with petroleum ether/EtOAc; 20/1). (500 MHz, CDCl3): δ 9.08–9.05 (m, 2H), 8.40 (d, J = 8.0 Hz, 1H),
Yellow solid (37 mg, 28%); mp = 79–80 °C; Rf (light petroleum/ 7.79 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 9.0, 4.0 Hz, 1H), 6.91–6.90
EtOAc = 3/1) 0.41. FT-IR (ATR, neat): 3049, 1508, 1379, 1306, (m, 1H), 6.44 (dd, J = 3.5, 2.0 Hz, 1H), 6.34–6.33 (m, 1H), 3.52
1
932, 822, 740 cm−1. H NMR (500 MHz, CDCl3): δ 9.07 (dd, J = (s, 3H). 13C NMR (125 MHz, CDCl3): δ 151.1, 146.3, 144.3,
4.2, 1.8 Hz, 1H), 8.21 (dd, J = 8.2, 1.9 Hz, 1H), 8.17 (dd, J = 7.3, 140.0, 132.0, 130.8, 129.2, 125.2, 124.4, 123.6, 121.7, 112.4,
1.4 Hz, 1H), 8.10 (s, 1H), 7.90–7.85 (m, 2H), 7.82 (dd, J = 8.1, 108.5, 35.8. HRMS (ESI+): m/z calcd for C14H12N3O2 (M + H)+:
1.4 Hz, 1H), 7.62–7.59 (m, 1H), 7.48 (dd, J = 8.2, 4.1 Hz, 1H), 254.0924; found: 254.0925. Elemental analysis calcd for
7.38–7.31 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 149.7, 145.1, C14H11N3O2: C, 66.40; H, 4.38; N, 16.59; found: C, 66.17; H,
141.6, 140.4, 139.7, 136.5, 133.0, 129.2, 128.8, 128.1, 126.4, 4.11; N, 16.37.
124.2, 124.1, 123.9, 123.7, 121.9, 121.4. HRMS (ESI+): m/z calcd
General procedure for Suzuki–Miyaura coupling (4k–r). The
for C17H12NS (M + H)+: 262.0685; found: 262.0683. Elemental corresponding quinoline (1, 2) (0.25 mmol), boronic acid
analysis calcd for C17H11NS: C, 78.13; H, 4.28; N, 5.36; found: (6a–g) (0.375 mmol), Pd(OAc)2 (2.8 mg, 0.0125 mmol), PPh3
C, 77.64; H, 3.87; N, 5.21.
(6.6 mg, 0.025 mmol) and K2CO3 (69 mg, 0.5 mmol) were dis-
8-(Furan-2-yl)-5-nitroquinoline (4g). Radial chromatography solved in a mixture of 1,4-dioxane (0.8 mL) and water (0.2 mL).
on silica gel (eluting with petroleum ether/EtOAc; 20/1). Yellow The reaction mixture was stirred in a sealed glass tube at
solid (53 mg, 44%); mp = 153–156 °C; Rf (light petroleum/ 100 °C for 24 h under an inert atmosphere. The mixture was
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allowed to cool to r.t. to which water was added (3 mL) and the
5-Nitro-8-(thiophen-3-yl)quinoline (4o). Radial chromato-
product was extracted into dichloromethane (2 × 3 mL). The graphy on silica gel (eluting with petroleum ether/EtOAc; 20/1).
combined organic layers were dried (Na2SO4) and filtered, and Yellow solid (58 mg, 90%); mp = 143–145 °C; Rf (light pet-
the solvent was evaporated under reduced pressure. The crude roleum/EtOAc = 3/1) 0.44. FT-IR (ATR, neat): 3089, 1492, 1326,
product was purified by radial chromatography to yield pure 1291, 1208, 1140, 851, 793, 774 cm−1
.
1H NMR (500 MHz,
product 4.
CDCl3): δ 9.11–9.07 (m, 2H), 8.40 (d, J = 8.2 Hz, 1H), 8.06 (dd,
8-(Furan-3-yl)quinoline (4k). Radial chromatography on J = 3.0, 1.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.68–7.63 (m, 2H),
silica gel (eluting with petroleum ether/EtOAc; 50/1). Colour- 7.49–7.46 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 150.9, 145.5,
less oil (42 mg, 85%); Rf (light petroleum/EtOAc = 5/3) 0.44. 144.1, 142.0, 138.0, 132.1, 129.6, 127.4, 127.2, 125.2, 124.6,
FT-IR (ATR, neat): 3045, 1511, 1497, 1158, 1028, 871, 794, 756, 123.6, 121.9. HRMS (ESI+): m/z calcd for C13H9N2O2S (M + H)+:
1
645 cm−1. H NMR (500 MHz, CDCl3): δ 8.98 (dd, J = 4.1, 1.8 257.0379; found: 257.0376. Elemental analysis calcd for
Hz, 1H), 8.56 (s, 1H), 8.18 (dd, J = 8.3, 1.8 Hz, 1H), 7.87 (dd, J = C13H8N2O2S: C, 60.93; H, 3.15; N, 10.93; found: C, 60.66; H,
7.2, 1.4 Hz, 1H), 7.73 (dd, J = 8.2, 1.4 Hz, 1H) 7.57–7.54 (m, 2.94; N, 10.84.
2H), 7.43 (dd, J = 8.2, 4.1 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H). 13C
5-Nitro-8-(1H-pyrrol-2-yl)quinoline (4p). Radial chromato-
NMR (125 MHz, CDCl3): δ 149.7, 145.7, 143.1, 142.3, 136.4, graphy on silica gel (eluting with petroleum ether/dichloro-
131.5, 128.8, 127.8, 126.8, 126.4, 122.8, 121.1, 110.6. HRMS methane; 2/1). Orange solid (37 mg, 62%); mp = 147–148 °C;
(ESI+): m/z calcd for C13H10NO (M + H)+: 196.0757; found: Rf (light petroleum/EtOAc = 3/1) 0.48. FT-IR (ATR, neat): 3307,
196.0757.
1562, 1494, 1311, 1044, 857, 743 cm−1 1H NMR (500 MHz,
.
8-(Thiophen-3-yl)quinoline (4l). Radial chromatography on CDCl3): δ 12.68 (s, 1H), 9.25 (dd, J = 9.0, 1.5 Hz, 1H), 8.99 (dd,
silica gel (eluting with petroleum ether/EtOAc; 20/1). Yellow oil J = 4.0, 1.5 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.5 Hz,
(37 mg, 70%); Rf (light petroleum/EtOAc = 5/3) 0.48. FT-IR 1H), 7.66 (dd, J = 9.0, 4.0 Hz, 1H), 7.14–7.13 (m, 1H), 7.09–7.07
(ATR, neat): 3034, 1607, 1529, 1133, 866, 830, 793, 754 cm−1
.
(m, 1H), 6.41–6.39 (m, 1H). 13C NMR (125 MHz, CDCl3):
1H NMR (500 MHz, CDCl3): δ 8.97 (dd, J = 4.1, 1.8 Hz, 1H), δ 149.1, 143.7, 140.9, 135.8, 133.2, 130.1, 126.1, 123.6, 122.9,
8.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.89 (dd, J = 3.0, 1.3 Hz, 1H), 7.85 122.3, 122.2, 111.8, 110.4. HRMS (ESI+): m/z calcd for
(dd, J = 7.2, 1.5 Hz, 1H), 7.75 (dd, J = 8.1, 1.4 Hz, 1H), 7.66 (dd, C13H10N3O2 (M + H)+: 240.0768; found: 240.0766. Elemental
J = 5.0, 1.4 Hz, 1H), 7.56–7.53 (m, 1H), 7.42 (dd, J = 5.0, 3.0 Hz, analysis calcd for C13H9N3O2: C, 65.27; H, 3.79; N, 17.56;
1H), 7.39 (dd, J = 8.2, 4.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): found: C, 65.11; H, 3.69; N, 17.13.
δ 150.0, 145.8, 139.5, 136.3, 135.1, 129.7, 129.4, 128.8, 127.3,
8-(Benzofuran-2-yl)-5-nitroquinoline (4q). Radial chromato-
126.3, 124.7, 124.5, 121.0. HRMS (ESI+): m/z calcd for graphy on silica gel (eluting with petroleum ether/EtOAc; 20/1).
C13H10NS (M + H)+: 212.0528; found: 212.0530. Elemental Yellow solid (57 mg, 79%); mp = 183–185 °C; Rf (light pet-
analysis calcd for C13H9NS: C, 73.90; H, 4.29; N, 6.63; found: roleum/EtOAc = 3/1) 0.49. FT-IR (ATR, neat): 2919, 1562, 1499,
1
C, 73.75; H, 4.16; N, 6.57.
1449, 1312, 834, 812, 740 cm−1. H NMR (500 MHz, CDCl3): δ
8-(1H-Pyrrol-2-yl)quinoline (4m). Radial chromatography on 9.15–9.14 (m, 1H), 9.12–9.10 (m, 1H), 8.55–8.53 (m, 2H),
silica gel (eluting with petroleum ether/EtOAc; 20/1). Yellow 8.47–8.45 (m, 1H), 7.74–7.70 (m, 2H), 7.59–7.58 (m, 1H),
solid (28 mg, 57%); mp = 86–90 °C; Rf (light petroleum/EtOAc 7.41–7.38 (m, 1H), 7.31–7.28 (m, 1H). 13C NMR (125 MHz,
= 10/1) 0.46. FT-IR (ATR, neat): 3305, 1775, 1498, 1312, 1111, CDCl3): δ 154.7, 151.1, 150.7, 144.4, 144.1, 134.6, 132.4, 129.5,
1081, 802, 721 cm−1 1H NMR (500 MHz, CDCl3): δ 12.62 (s, 126.0, 124.8 (2C), 123.8, 123.2, 122.3, 121.7, 113.6, 111.2.
.
1H), 8.90 (dd, J = 4.2, 1.9 Hz, 1H), 8.18–8.11 (m, 2H), 7.61–7.58 HRMS (ESI+): m/z calcd for C17H11N2O3 (M + H)+: 291.0764;
(m, 1H), 7.55–7.50 (m, 1H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), found: 291.0766.
7.03–7.01 (m, 1H), 6.91–6.89 (m, 1H), 6.35–6.32 (m, 1H). 13C
8-(Benzo[b]thiophen-2-yl)-5-nitroquinoline
(4r). Radial
NMR (125 MHz, CDCl3): δ 148.5, 144.6, 137.1, 131.6, 129.1, 129.0, chromatography on silica gel (eluting with petroleum ether/
126.8, 125.0, 124.9, 120.8, 119.1, 108.9, 107.0. HRMS (ESI+): m/z EtOAc; 20/1). Yellow solid (53 mg, 69%); mp = 149–152 °C; Rf
calcd for C13H11N2 (M + H)+: 195.0917; found: 195.0916.
(light petroleum/EtOAc = 5/3) 0.49. FT-IR (ATR, neat): 3051,
8-(Furan-3-yl)-5-nitroquinoline (4n). Radial chromatography 1509, 1492, 1329, 1303, 815, 791, 739 cm−1 1H NMR
.
on silica gel (eluting with petroleum ether/EtOAc; 20/1). Yellow (500 MHz, CDCl3): δ 9.17–9.14 (m, 2H), 8.46 (d, J = 8.5 Hz, 1H),
solid (51 mg, 85%); mp = 117–119 °C; Rf (light petroleum/ 8.28 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.93–7.90 (m, 2H), 7.73
EtOAc = 3/1) 0.49. FT-IR (ATR, neat): 3121, 1510, 1500, 1315, (dd, J = 9.0, 4.0 Hz, 1H), 7.41–7.39 (m, 2H). 13C NMR
1
1158, 1143, 868, 808 cm−1. H NMR (500 MHz, CDCl3): δ 9.09 (125 MHz, CDCl3): δ 150.1, 144.4, 143.8, 143.0, 139.8, 138.9,
(dd, J = 8.9, 1.7 Hz, 1H), 9.07–9.05 (m, 1H), 8.74 (s, 1H), 8.39 138.3, 132.3, 126.2, 126.1, 125.4, 124.6, 124.5, 124.3, 124.0,
(d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.2, 1H), 7.66 (dd, J = 8.9, 4.1 Hz, 122.0, 121.9. HRMS (ESI+): m/z calcd for C17H11N2O2S (M +
1H), 7.59–7.58 (m, 1H), 7.01–7.00 (m, 1H). 13C NMR (125 MHz, H)+: 307.0536; found: 307.0538.
CDCl3): δ 150.4, 145.5, 145.1, 143.4, 142.9, 138.9, 132.3, 125.2,
Procedure for Suzuki–Miyaura coupling with potassium
thiophene-2-trifluoroborate
124.9, 123.7, 121.8 (2C), 110.2. HRMS (ESI+): m/z calcd for
C13H9N2O3 (M + H)+: 241.0608; found: 241.0611. Elemental
analysis calcd for C13H8N2O3: C, 65.00; H, 3.36; N, 11.66; Quinoline 1 (0.50 mmol), potassium thiophene-2-trifluoro-
found: C, 64.67; H, 3.50; N, 12.04.
borate (1.50 mmol) and the Pd catalyst A (36 mg, 0.05 mmol)
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were dissolved in 1,4-dioxane. The reaction mixture was stirred 10/1). Yellow solid (77 mg, 61%); mp = 217–220 °C; Rf (light
in a sealed glass tube at 80 °C for 48 h under an inert atmos- petroleum/EtOAc = 5/3) 0.31. FT-IR (ATR, neat): 3124, 1771,
phere. The mixture was allowed to cool to r.t. to which water 1753, 1240, 1056, 831, 693 cm−1. 1H NMR (500 MHz, CDCl3): δ
was added (5 mL) and the product was further extracted into 8.88 (dd, J = 4.0, 2.0 Hz, 1H), 8.26 (dd, J = 8.5, 2.0 Hz, 1H),
dichloromethane (2 × 5 mL). The combined organic layers 8.01–7.99 (AA′BB′, J = 9.0 Hz, 2H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H),
were dried (Na2SO4),and filtered, and the solvent was evapor- 7.73 (dd, J = 7.0, 1.5 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.61–7.58
ated under reduced pressure. The crude product was purified (m, 1H), 7.50–7.44 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H). 13C NMR
by radial chromatography to yield pure product 4b.
(125 MHz, CDCl3): δ 150.7, 147.4, 146.3, 146.0, 143.0, 137.2,
136.5, 132.9, 131.0, 128.9, 128.6, 126.4, 125.6 (2C), 123.7, 123.6
(2C), 121.5, 116.7. HRMS (ESI+): m/z calcd for C19H13N2O3 (M +
H)+: 317.0921; found: 317.0920.
General procedure for one-pot sequential Suzuki–Miyaura
coupling and direct C–H functionalization
The corresponding quinoline (1, 2) (0.50 mmol), boronic acid
4-[3-(Quinolin-8-yl)furan-2-yl]benzonitrile
(7c). Radial
6 (0.75 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (13.1 mg, chromatography on silica gel (eluting with petroleum ether/
0.05 mmol) and K2CO3 (207 mg, 1.5 mmol) were dissolved in a EtOAc; 10/1). Orange solid (52 mg, 44%); mp = 106–110 °C; Rf
mixture of 1,4-dioxane (1.6 mL) and water (0.4 mL). The reac- (light petroleum/EtOAc = 5/3) 0.40. FT-IR (ATR, neat): 3108,
tion mixture was stirred in a sealed glass tube at 100 °C for 2219, 1605, 1499, 1063, 828, 797, 753 cm−1
.
1H NMR
24 h under an inert atmosphere. After allowing the mixture to (500 MHz, CDCl3): δ 8.89 (dd, J = 4.0, 2.0 Hz, 1H), 8.24 (dd, J =
cool to r.t. the glass tube was opened to which the aryl 8.5, 2.0 Hz, 1H), 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (dd, J = 7.0,
bromide (0.40 mmol) and Pd(OAc)2 (5.6 mg, 0.025 mmol) were 1.5 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.59–7.56 (m, 1H),
added. The reaction mixture was again sealed and further 7.46–7.40 (m, 5H), 6.75 (d, J = 2.0 Hz, 1H). 13C NMR (125 MHz,
stirred at 120 °C for 24 h under an inert atmosphere. The CDCl3): δ 150.6, 147.6, 146.3, 142.6, 136.4, 135.4, 133.0, 132.0
mixture was allowed to cool to r.t. to which water was added (2C), 131.0, 128.9, 128.5, 126.4, 125.6 (2C), 122.9, 121.5, 119.0,
(5 mL) and the product was further extracted with dichloro- 116.5, 109.8. HRMS (ESI+): m/z calcd for C20H13N2O (M + H)+:
methane (2 × 5 mL). The combined organic layers were dried 297.1022; found: 297.1022.
(Na2SO4), filtered and the solvent was evaporated under
reduced pressure. The crude product was purified by radial Radial chromatography on silica gel (eluting with petroleum
chromatography to yield pure product 7. ether/EtOAc; 10/1). Yellow solid (66 mg, 50%); mp
8,8′-(Thiophene-2,3-diyl)diquinoline (4l′). Radial chromato- 207–210 °C; Rf (light petroleum/EtOAc = 5/3) 0.38. FT-IR (ATR,
graphy on silica gel (eluting with petroleum ether/EtOAc; 5/1). neat): 3043, 1675, 1599, 1357, 1265, 828, 794, 723 cm−1 1H
1-{4-[3-(Quinolin-8-yl)thiophen-2-yl]phenyl}ethan-1-one (7d).
=
.
Yellow solid (3 mg, 2%); mp = 242–247 °C; Rf (light petroleum/ NMR (500 MHz, CDCl3): δ 8.90 (dd, J = 4.0, 2.0 Hz, 1H), 8.20
EtOAc = 1/1) 0.48. FT-IR (ATR, neat): 3048, 1572, 1492, 905, (dd, J = 8.5, 2.0 Hz, 1H), 7.81 (dd, J = 8.0, 2.0 Hz, 1H),
1
900, 825, 785, 750, 729, 667 cm−1. H NMR (500 MHz, CDCl3): 7.71–7.70 (AA′BB′, J = 8.5 Hz, 2H), 7.49–7.48 (m, 1H), 7.46–7.40
δ 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.85 (dd, J = 4.2, 1.8 Hz, 1H), (m, 3H), 7.35 (d, J = 5.0 Hz, 1H), 7.28–7.26 (m, 2H), 2.51 (s,
8.13–8.09 (m, 2H), 7.65–7.60 (m, 3H), 7.47 (d, J = 5.2 Hz, 1H), 3H). 13C NMR (125 MHz, CDCl3): δ 197.6, 150.4, 146.7, 139.6,
7.41 (dd, J = 7.2, 1.4 Hz, 1H), 7.38–7.33 (m, 3H), 7.21–7.18 (m, 139.1, 137.1, 136.2, 135.6, 135.2, 132.7, 131.7, 130.9, 128.8
2H). 13C NMR (125 MHz, CDCl3): δ 149.9, 149.8, 146.8, 146.6, (2C), 128.3 (2C), 127.8, 126.2, 124.6, 121.2, 26.5. HRMS (ESI+):
138.3, 136.9, 136.4, 136.0 (2C), 133.8, 132.3, 131.5, 131.2, m/z calcd for C21H16NOS (M + H)+: 330.0947; found: 330.0945.
128.5, 128.4, 127.5, 127.0, 126.0, 125.9, 125.3, 120.9, 120.8.
1-{4-[3-(5-Nitroquinolin-8-yl)furan-2-yl]phenyl}ethan-1-one
HRMS (ESI+): m/z calcd for C22H15N2S (M + H)+: 339.0950; (7e). Radial chromatography on silica gel (eluting with pet-
found: 339.0951.
roleum ether/EtOAc; 10/1). Yellow solid (69 mg, 48%); mp =
1-{4-[3-(Quinolin-8-yl)furan-2-yl]phenyl}ethan-1-one
(7a). 218–220 °C; Rf (light petroleum/EtOAc = 5/3) 0.39. FT-IR (ATR,
1
Radial chromatography on silica gel (eluting with petroleum neat): 3137, 1673, 1601, 1515, 1500, 1335, 1250, 812 cm−1. H
ether/EtOAc; 10/1). Yellow solid (100 mg, 80%); mp
180–185 °C; Rf (light petroleum/EtOAc = 5/3) 0.48. FT-IR (ATR, (dd, J = 4.1, 1.7 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.81–7.78 (m,
neat): 2923, 1671, 1602, 1357, 1261, 831, 795, 730 cm−1 1H 3H), 7.70 (d, J = 1.8, 1H), 7.86 (dd, J = 8.9, 4.1 Hz, 1H),
=
NMR (500 MHz, CDCl3): δ 9.10 (dd, J = 8.9, 1.7 Hz, 1H), 8.99
.
NMR (500 MHz, CDCl3): δ 8.91 (dd, J = 4.0, 2.0 Hz, 1H), 8.24 7.43–7.42 (m, 2H), 6.79 (d, J = 1.8 Hz, 1H), 2.54 (s, 3H). 13C
(dd, J = 8.5, 2.0 Hz, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), NMR (125 MHz, CDCl3): δ 197.3, 151.3, 149.5, 146.2, 145.0,
7.75–7.74 (AA′BB′, J = 8.5 Hz, 2H), 7.71 (dd, J = 7.0, 1.5 Hz, 1H), 142.6, 141.0, 135.7, 134.8, 132.2, 129.2, 128.5 (2C), 125.9 (2C),
7.67 (d, J = 2.0 Hz, 1H), 7.57–7.54 (m, 1H), 7.46–7.43 (m, 3H), 124.3, 124.1, 121.9, 120.7, 116.0, 26.5. HRMS (ESI+): m/z calcd
6.76 (d, J = 1.7 Hz, 1H), 2.52 (s, 3H). 13C NMR (125 MHz, for C21H15N2O4 (M + H)+: 359.1026; found: 359.1023. Elemen-
CDCl3): δ 197.5, 150.5, 148.5, 146.5, 142.2, 136.4, 135.6, 135.1, tal analysis calcd for C21H14N2O4: C, 70.39; H, 3.94; N, 7.82;
133.3, 131.1, 128.9, 128.3, 128.2, 126.4, 125.3, 122.2, 121.4, found: C, 70.40; H, 3.70; N, 7.52.
116.4, 26.5. HRMS (ESI+): m/z calcd for C21H16NO2 (M + H)+:
5-Nitro-8-[2-(4-nitrophenyl)furan-3-yl]quinoline (7f). Radial
314.1176; found: 314.1171.
chromatography on silica gel (eluting with petroleum ether/
8-[2-(4-Nitrophenyl)furan-3-yl]quinoline (7b). Radial chromato- EtOAc; 10/1). Yellow solid (101 mg, 70%); mp = 254–256 °C; Rf
graphy on silica gel (eluting with petroleum ether/EtOAc; (light petroleum/EtOAc = 5/3) 0.51. FT-IR (ATR, neat): 3091,
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1595, 1500, 1324, 1103, 1072, 851, 795, 705 cm−1 1H NMR 838, 787 cm−1. H NMR (500 MHz, CDCl3): δ 9.12 (dd, J = 8.9,
.
(500 MHz, CDCl3): δ 9.10 (dd, J = 8.9, 1.7 Hz, 1H), 8.96 (dd, J = 1.7 Hz, 1H), 9.01 (dd, J = 4.1, 1.7 Hz, 1H), 8.39 (d, J = 8.0 Hz,
4.1, 1.7 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.06–8.04 (m, 2H), 1H), 8.06–8.04 (m, 2H), 7.91–7.89 (m, 2H), 7.86 (d, J = 8.0, 1H),
7.82 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 7.84–7.82 (m, 2H), 7.71 (dd, J = 8.9, 4.1 Hz, 1H), 7.52–7.50 (m,
8.9, 4.1 Hz, 1H), 7.48–7.46 (m, 2H), 6.79 (d, J = 1.9 Hz, 1H). 13
C
2H), 7.19 (s, 1H), 2.65 (s, 3H), 2.56 (s, 3H). 13C NMR (125 MHz,
NMR (125 MHz, CDCl3): δ 151.5, 148.3, 146.5, 146.0, 145.3, CDCl3): δ 197.3, 197.2, 152.5, 151.5, 149.9, 146.1, 145.3, 140.4,
143.3, 140.4, 136.6, 132.3, 129.1, 126.1 (2C), 124.3, 124.2, 123.9 136.1, 136.0, 134.3, 134.0, 132.3, 129.2, 129.0 (2C), 128.6 (2C),
(2C), 122.0, 121.9, 116.3. HRMS (ESI+): m/z calcd for 125.9 (2C), 124.3, 124.2, 124.0 (2C), 123.0, 121.9, 113.6, 26.6,
C19H12N3O5 (M + H)+: 362.0771; found: 362.0770.
26.5. HRMS (ESI+): m/z calcd for C29H21N2O5 (M + H)+:
4-[3-(5-Nitroquinolin-8-yl)furan-2-yl]benzonitrile (7g). Radial 477.1445; found: 477.1443. Elemental analysis calcd for
chromatography on silica gel (eluting with petroleum ether/ C29H20N2O5: C, 73.10; H, 4.23; N, 5.88; found: C, 73.18; H,
EtOAc; 10/1). Yellow solid (71 mg, 52%); mp = 157–161 °C; Rf 3.89; N, 5.59.
(light petroleum/EtOAc = 5/3) 0.46. FT-IR (ATR, neat): 3084,
2221, 1604, 1504, 1328, 1068, 896, 840, 786, 728 cm−1
1-{4-[2-(Quinolin-8-yl)benzofuran-3-yl]phenyl}ethan-1-one
.
1H (7i). Radial chromatography on silica gel (eluting with pet-
NMR (500 MHz, CDCl3): δ 9.09 (dd, J = 8.9, 1.6 Hz, 1H), 8.96 roleum ether/EtOAc; 10/1). Light yellow solid (103 mg, 71%);
(dd, J = 4.2, 1.6 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 mp = 153–155 °C; Rf (light petroleum/EtOAc = 5/3) 0.63. FT-IR
Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 8.9, 4.2 Hz, 1H), (ATR, neat): 2917, 1678, 1604, 1266, 1182, 957, 831, 795, 750,
1
7.48–7.46 (m, 2H), 7.42–7.40 (m, 2H), 6.78 (d, J = 1.7 Hz, 1H). 727 cm−1. H NMR (500 MHz, CDCl3): δ 8.79 (dd, J = 4.0, 2.0
13C NMR (125 MHz, CDCl3): δ 151.4, 148.5, 146.0, 145.2, 143.0, Hz, 1H), 8.20 (dd, J = 8.5, 2.0 Hz, 1H), 7.92 (dd, J = 8.0, 1.5 Hz,
140.5, 134.7, 132.2, 132.1 (2C), 129.0, 126.0 (2C), 124.3, 124.2, 1H), 7.84–7.77 (m, 4H), 7.64 (d, J = 8.0 Hz, 1H), 7.57–7.54 (m,
121.9, 121.3, 118.7, 116.2, 110.7. HRMS (ESI+): m/z calcd for 1H), 7.46–7.44 (AA′BB′, J = 8.5 Hz, 2H), 7.41–7.38 (m, 2H),
C20H12N3O3 (M + H)+: 342.0873; found: 342.0870.
7.35–7.32 (m, 1H), 2.56 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
1-{4-[3-(5-Nitroquinolin-8-yl)thiophen-2-yl]phenyl}ethan-1-one 197.7, 155.1, 151.4, 150.8, 146.5, 138.6, 136.2, 135.3, 132.5,
(7h). Radial chromatography on silica gel (eluting with pet- 129.9, 129.0 (2C), 128.6, 128.5 (2C), 128.3, 127.4, 126.1, 124.8,
roleum ether/EtOAc; 10/1). Orange solid (46 mg, 31%); mp = 123.2, 121.5, 120.0, 119.5, 111.7, 26.5. HRMS (ESI+): m/z calcd
205–209 °C; Rf (light petroleum/EtOAc = 5/3) 0.42. FT-IR (ATR, for C25H18NO2 (M + H)+: 364.1332; found: 364.1328. Elemental
neat): 3100, 1675, 1597, 1513, 1333, 1263, 864, 797, 736, analysis calcd for C25H17NO2: C, 82.63; H, 4.72; N, 3.85; found:
1
725 cm−1. H NMR (500 MHz, CDCl3): δ 9.06 (dd, J = 9.0, 2.0 C, 82.42; H, 4.51; N, 3.76.
Hz, 1H), 8.98 (dd, J = 4.0, 2.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H),
8-[3-(4-Nitrophenyl)benzofuran-2-yl]quinoline (7j). Radial
7.76–7.74 (AA′BB′, J = 8.5 Hz, 2H), 7.64 (dd, J = 9.0, 4.0 Hz, 1H), chromatography on silica gel (eluting with petroleum ether/
7.55 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 5.0 Hz, 1H), 7.34 (d, J = EtOAc; 20/1). Yellow solid (92 mg, 63%); mp = 71–76 °C;
5.0 Hz, 1H), 7.26–7.24 (AA′BB′, J = 8.5 Hz, 2H), 2.53 (s, 3H). Rf (light petroleum/EtOAc = 5/3) 0.60. FT-IR (ATR, neat):
13C NMR (125 MHz, CDCl3): δ 197.2, 151.2, 146.3, 144.7, 143.0, 3065, 1596, 1510, 1341, 1104, 851, 792, 746 cm−1 1H NMR
.
140.8, 138.8, 135.7, 135.3, 132.3, 132.1, 129.8, 129.0 (2C), (500 MHz, CDCl3): δ 8.71 (dd, J = 4.0, 2.0 Hz, 1H), 8.21
128.6 (2C), 125.1, 124.2, 123.9, 121.8, 26.5. HRMS (ESI+): (dd, J = 8.5, 2.0 Hz, 1H), 8.10–8.08 (AA′BB′, J = 9.0 Hz, 2H), 7.96
m/z calcd for C21H15N2O3S (M
375.0789.
4,4′-[3-(Quinolin-8-yl)furan-2,5-diyl]dibenzonitrile
+
H)+: 375.0798; found: (dd, J = 8.0, 1.5 Hz, 1H), 7.89 (dd, J = 7.0, 1.5 Hz, 1H), 7.76 (d,
J = 7.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.62–7.59 (m, 1H),
(7ca). 7.51–7.49 (AA′BB′, J = 9.0 Hz, 2H), 7.44–7-35 (m, 3H). 13C NMR
Radial chromatography on silica gel (eluting with petroleum (125 MHz, CDCl3): δ 155.1, 151.7, 150.7, 146.3, 146.0, 140.9,
ether/EtOAc; 5/1). Orange solid (41 mg, 26%); mp > 250 °C; Rf 136.3, 132.3, 130.2, 129.4, 129.3 (2C), 128.7, 128.0, 126.2,
(light petroleum/EtOAc = 1/1) 0.68. FT-IR (ATR, neat): 3117, 125.1, 123.7 (2C), 123.4, 121.7, 119.7, 118.7, 111.8. HRMS
1
2221, 1599, 1497, 938, 827, 790, 758 cm−1. H NMR (500 MHz, (ESI+): m/z calcd for C23H15N2O3 (M + H)+: 367.1077; found:
CDCl3): δ 8.90 (dd, J = 4.0, 2.0 Hz, 1H), 8.28 (dd, J = 8.5, 2.0 Hz, 367.1073.
1H), 7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.89–7.87 (AA′BB′, J = 8.5 Hz,
4-[2-(Quinolin-8-yl)benzofuran-3-yl]benzonitrile (7k). Radial
2H), 7.75 (dd, J = 7.0, 1.5 Hz, 1H), 7.73–7.71 (AA′BB′, J = 8.5 Hz, chromatography on silica gel (eluting with petroleum ether/
2H), 7.63–7.60 (m, 1H), 7.52–7.45 (m, 5H), 7.17 (s, 1H). 13C EtOAc; 10/1). Yellow solid (100 mg, 72%); mp = 89–93 °C; Rf
NMR (125 MHz, CDCl3): δ 151.5, 150.8, 148.6, 146.2, 136.6, (light petroleum/EtOAc = 5/3) 0.58. FT-IR (ATR, neat): 3047,
1
134.6, 134.1, 132.7 (2C), 132.2, 132.1 (2C), 131.0, 129.0, 2224, 1607, 1494, 1451, 960, 829, 793, 745, 727 cm−1. H NMR
128.9126.5, 125.8 (2C), 125.4, 124.3 (2C), 121.7, 118.9, 118.8, (500 MHz, CDCl3): δ 8.72 (dd, J = 4.0, 2.0 Hz, 1H), 8.20 (dd, J =
114.9, 110.9, 110.5. HRMS (ESI+): m/z calcd for C27H16N3O 8.5, 2.0 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.87 (dd, J = 7.0,
(M + H)+: 398.1288; found: 398.1282.
1.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0, 1H),
1,1′-{[3-(5-Nitroquinolin-8-yl)furan-2,5-diyl]bis(4,1-phenylene)} 7.61–7.58 (m, 1H), 7.52–7.50 (AA′BB′, J = 8.5 Hz, 2H), 7.45–7.43
bis(ethan-1-one) (7ea). Radial chromatography on silica gel (AA′BB′, J = 8.5 Hz, 2H), 7.42–7.39 (m, 2H), 7.36–7-33 (m, 1H).
(eluting with petroleum ether/EtOAc; 5/1). Yellow solid (67 mg, 13C NMR (125 MHz, CDCl3): δ 155.1, 151.4, 150.6, 146.0, 138.8,
35%); mp = 220–224 °C; Rf (light petroleum/EtOAc = 5/3) 0.27. 136.2, 132.3, 132.1 (2C), 130.0, 129.5, 129.4 (2C), 128.7, 128.0,
FT-IR (ATR, neat): 3131, 1669, 1598, 1505, 1328, 1261, 1181, 126.1, 125.0, 123.3, 121.6, 119.7, 119.0, 118.9, 111.8, 110.0.
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HRMS (ESI+): m/z calcd for C24H15N2O (M + H)+: 347.1179; 135.6, 131.9, 130.0, 129.0 (2C), 128.6 (2C), 128.2, 125.8, 124.1,
found: 347.1174.
124.0, 123.6, 121.9, 121.6, 120.4, 111.8, 26.6. HRMS (ESI+): m/z
8-[3-(4-Methoxyphenyl)benzofuran-2-yl]quinoline (7l). Radial calcd for C25H17N2O4 (M + H)+: 409.1183; found: 409.1186.
chromatography on silica gel (eluting with petroleum ether/ Elemental analysis calcd for C25H16N2O4: C, 73.52; H, 3.95; N,
EtOAc; 10/1). Yellow solid (112 mg, 80%); mp = 51–57 °C; Rf 6.86; found: C, 73.22; H, 3.68; N, 6.46.
(light petroleum/EtOAc = 5/1) 0.54. FT-IR (ATR, neat): 2834,
1512, 1450, 1286, 1244, 1171, 1017, 828, 792, 744 cm−1
5-Nitro-8-[3-(4-nitrophenyl)benzofuran-2-yl]quinoline (7p).
.
1H Radial chromatography on silica gel (eluting with petroleum
NMR (500 MHz, CDCl3): δ 8.88 (dd, J = 4.0, 2.0 Hz, 1H), 8.18 ether/EtOAc; 10/1). Yellow solid (148 mg, 90%); mp
(dd, J = 8.5, 2.0 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 189–194 °C; Rf (light petroleum/EtOAc = 7/1) 0.44. FT-IR (ATR,
7.76–7.75 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.52–7.49 (m, 1H), neat): 3080, 1597, 1508, 1492, 1340, 854, 746, 703 cm−1 1H
=
.
7.40 (dd, J = 8.5, 4.0 Hz, 1H), 7.37–7.34 (m, 1H), 7.31–7.28 (m, NMR (500 MHz, CDCl3): δ 9.00 (dd, J = 9.0, 2.0 Hz, 1H), 8.64
3H), 6.80–6.79 (AA′BB′, J = 8.5 Hz, 2H), 3.76 (s, 3H). 13C NMR (dd, J = 4.0, 1.5 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.13 (AA′BB′,
(125 MHz, CDCl3): δ 158.4, 155.0, 150.8, 150.2, 146.9, 136.1, J = 9.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H),
132.7, 130.4, 130.2 (2C), 129.4, 129.0, 128.6, 126.0, 125.3, 7.67 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 9.0, 4.0 Hz, 1H), 7.49–7.45
124.4, 122.7, 121.4, 120.2, 119.8, 113.9 (2C), 111.6, 55.1. HRMS (m, 3H), 7.38 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 155.2,
(ESI+): m/z calcd for C24H18NO2 (M + H)+: 352.1332; found: 151.0, 148.9, 146.6, 145.9, 145.2, 140.6, 136.1, 132.0, 129.9,
352.1329.
129.5 (2C), 128.0, 126.0, 124.2, 124.0, 123.8 (3C), 121.6, 121.0,
4-[2-(Quinolin-8-yl)benzo[b]thiophen-3-yl]benzonitrile (7m). 120.1, 111.9. HRMS (ESI+): m/z calcd for C23H14N3O5 (M + H)+:
Radial chromatography on silica gel (eluting with petroleum 409.1183; found: 409.1186.
ether/EtOAc; 10/1). Yellow solid (93 mg, 64%); mp
=
4-[1-Methyl-5-(quinolin-8-yl)-1H-pyrrol-3-yl]benzonitrile (7q).
181–184 °C; Rf (light petroleum/EtOAc = 5/3) 0.58. FT-IR (ATR, Radial chromatography on silica gel (eluting with petroleum
neat): 3055, 2227, 1603, 1488, 1362, 969, 823, 788, 738 cm−1
.
ether/diethyl ether; 2/1). White solid (56 mg, 45%); mp =
1H NMR (500 MHz, CDCl3): δ 8.86 (dd, J = 4.0, 2.0 Hz, 1H), 136–141 °C; Rf (light petroleum/EtOAc = 5/3) 0.63. FT-IR (ATR,
8.17 (dd, J = 8.5, 2.0 Hz, 1H), 7.93–7.92 (m, 1H), 7.82 (dd, J = neat): 2918, 2212, 1601, 1345, 1178, 930, 844, 829, 797,
8.0, 1.5 Hz, 1H), 7.70–7.68 (m, 1H), 7.57 (dd, J = 7.0, 1.5 Hz, 714 cm−1. H NMR (500 MHz, CDCl3): δ 8.96 (dd, J = 4.0, 2.0
1
1H), 7.49–7.48 (AA′BB′, J = 8.5 Hz, 2H), 7.46–7.43 (m, 1H), Hz, 1H), 8.26 (dd, J = 8.5, 2.0 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz,
7.41–7.38 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 150.4, 146.5, 1H), 7.56–7.51 (m, 2H), 7.46 (dd, J = 8.5, 4.0 Hz, 1H), 7.30–7.28
141.0, 140.6, 138.8, 138.6, 136.2, 133.9, 132.9, 132.8, 131.9, (AA′BB′, J = 8.5 Hz, 2H), 7.09–7.08 (AA′BB′, J = 8.5 Hz, 2H), 6.88
130.7, 129.0, 128.5, 125.9, 124.8, 124.6, 122.6, 122.3, 121.4, (d, J = 3.0 Hz, 1H), 6.55 (d, J = 3 Hz, 1H), 3.35 (s, 3H). 13C NMR
118.9, 110.4. HRMS (ESI+): m/z calcd for C24H15N2S (M + H)+: (125 MHz, CDCl3): δ 151.0, 147.6, 141.8, 136.4, 133.4, 131.8
363.0950; found: 363.0949.
(2C), 131.7, 129.8, 129.1, 128.7, 127.3 (2C), 126.4, 123.1, 122.2,
8-[3-(4-Nitrophenyl)benzo[b]thiophen-2-yl]quinoline
(7n). 121.4, 119.6, 107.7, 107.4, 35.0. HRMS (ESI+): m/z calcd for
Radial chromatography on silica gel (eluting with petroleum C21H16N3 (M + H)+: 310.1339; found: 310.1337.
ether/EtOAc; 10/1). Yellow solid (87 mg, 57%); mp
=
1-{4-[1-Methyl-2-(quinolin-8-yl)-1H-pyrrol-3-yl]phenyl}ethan-
153–156 °C; Rf (light petroleum/EtOAc = 5/3) 0.63. FT-IR (ATR, 1-one (7s). Radial chromatography on silica gel (eluting with
neat): 2916, 1594, 1511, 1342, 1307, 1101, 824, 788, 735 cm−1
.
petroleum ether/EtOAc; 10/1). Yellow solid (100 mg, 77%); mp
1H NMR (500 MHz, CDCl3): δ 8.86 (dd, J = 4.0, 2.0 Hz, 1H), = 75–78 °C; Rf (light petroleum/EtOAc = 5/3) 0.46. FT-IR (ATR,
8.18 (dd, J = 8.5, 2.0 Hz, 1H), 8.07–8.05 (AA′BB′, J = 9.0 Hz, 2H), neat): 2923, 1670, 1597, 1354, 1265, 1223, 1182, 832, 796,
7.95–7.93 (m, 1H), 7.84 (dd, J = 8.0, 1.5 Hz, 1H), 7.72–7.70 (m, 726 cm−1 1H NMR (500 MHz, CDCl3): δ 8.98 (dd, J = 4.0,
.
1H), 7.60 (dd, J = 7.0, 1.5 Hz, 1H), 7.47–7.44 (m, 3H), 7.43–7.39 2.0 Hz, 1H), 8.26 (dd, J = 8.5, 2.0 Hz, 1H), 7.91 (dd, J = 8.0,
(m, 3H). 13C NMR (125 MHz, CDCl3): δ 150.5, 146.5, 143.1, 1.5 Hz, 1H), 7.65–7.63 (AA′BB′, J = 8.5 Hz, 2H), 7.56 (dd, J = 7.0,
140.6, 139.0, 138.8, 136.3, 133.6, 132.9, 132.7, 130.8 (3C), 1.5 Hz, 1H), 7.53–7.50 (m, 1H), 7.46 (dd, J = 8.5, 4.0 Hz, 1H),
129.1, 128.5, 126.0, 124.9, 124.7, 123.5 (2C), 122.6, 122.3, 7.11–7.09 (AA′BB′, J = 8.5 Hz, 2H), 6.88 (d, J = 3.0 Hz, 1H), 6.59
121.5. HRMS (ESI+): m/z calcd for C23H15N2O2S (M + H)+: (d, J = 3.0 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H). 13C NMR
383.0849; found: 383.0851.
(125 MHz, CDCl3): δ 197.7, 151.0, 147.8, 142.1, 136.4, 133.5,
1-{4-[2-(5-Nitroquinolin-8-yl)benzofuran-3-yl]phenyl}ethan-1- 133.4, 132.1, 129.6, 128.9, 128.7, 128.3 (2C), 126.9 (2C), 126.5,
one (7o). Radial chromatography on silica gel (eluting with 122.9, 122.8, 121.4, 107.8, 35.0, 26.4. HRMS (ESI+): m/z calcd
petroleum ether/EtOAc; 10/1). Yellow solid (158 mg, 97%); mp for C22H19N2O (M + H)+: 327.1492; found: 327.1488.
= 148–152 °C; Rf (light petroleum/EtOAc = 5/3) 0.63. FT-IR
1-{4-[2-(Quinolin-8-yl)thiophen-3-yl]phenyl}ethan-1-one (7t).
(ATR, neat): 1676, 1605, 1531, 1515, 1329, 1265, 953, 828, Radial chromatography on silica gel (eluting with petroleum
1
737 cm−1. H NMR (500 MHz, CDCl3): δ 8.99 (dd, J = 9.0, 2.0 ether/EtOAc; 10/1). Yellow solid (39 mg, 30%); mp
=
Hz, 1H), 8.72 (dd, J = 4.0, 2.0 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 122–123 °C; Rf (light petroleum/EtOAc = 5/1) 0.49. FT-IR (ATR,
8.00 (d, J = 8.0 Hz, 1H), 7.87–7.85 (AA′BB′, J = 8.5 Hz, 2H), 7.77 neat): 2918, 2850, 1671, 1594, 1493, 1358, 1264, 1109, 955, 829,
1
(d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 9.0, 4.0 759 cm−1. H NMR (500 MHz, CDCl3): δ 9.07 (dd, J = 4.0, 2.0
Hz, 1H), 7.46–7.35 (m, 4H), 2.57 (s, 3H). 13C NMR (125 MHz, Hz, 1H), 8.22 (dd, J = 8.0, 2.0 Hz, 1H), 8.14 (dd, J = 7.5, 1.5 Hz,
CDCl3): δ 197.5, 155.3, 151.1, 148.6, 145.8, 145.6, 138.2, 136.6, 1H), 8.01–7.99 (AA′BB′, J = 8.5 Hz, 2H), 7.83–7.78 (m, 4H),
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7.662–7.59 (m, 1H), 7.52–7.48 (m, 2H), 2.64 (s, 3H). 13C NMR and water (0.4 mL). The reaction mixture was stirred in a
(125 MHz, CDCl3): δ 197.4, 149.5, 145.0, 144.5, 140.9, 139.3, sealed glass tube at 100 °C for 24 h under an inert atmosphere.
136.5, 135.5, 132.6, 129.1 (2C), 128.8, 127.6 (2C), 127.5, 126.5, After allowing the mixture to cool to r.t. the glass tube was
125.4 (2C), 124.3, 121.4, 26.6. HRMS (ESI+): m/z calcd for opened to which 1-bromo-4-nitrobenzene (81 mg, 0.40 mmol)
C21H16NOS (M + H)+: 330.0947; found: 330.0944.
and Pd(OAc)2 (5.6 mg, 0.025 mmol) were added. The reaction
4,4′-[1-Methyl-5-(quinolin-8-yl)-1H-pyrrole-2,4-diyl]dibenzo- mixture was again sealed and further stirred at 120 °C for 24 h
nitrile (7qa). Radial chromatography on silica gel (eluting under an inert atmosphere. The mixture was allowed to cool to
with petroleum ether/diethyl ether; 1/1). Light yellow solid r.t. to which 4-bromoacetophenone (80 mg, 0.4 mmol) and
(57 mg, 35%); mp = 147–151 °C; Rf (light petroleum/EtOAc = Pd(OAc)2 (5.6 mg, 0.025 mmol) were added. The reaction
1/1) 0.44. FT-IR (ATR, neat): 2921, 2224, 1602, 1491, 1171, 913, mixture was sealed for the second time and further stirred at
1
836, 791, 729 cm−1. H NMR (500 MHz, CDCl3): δ 9.01 (dd, J = 120 °C for 24 h under an inert atmosphere. The mixture was
4.0, 2.0 Hz, 1H), 8.30 (dd, J = 8.5, 2.0 Hz, 1H), 7.97 (dd, J = 8.0, allowed to cool to r.t. to which water was added (5 mL) and the
2.0 Hz, 1H), 7.75–7.73 (AA′BB′, J = 8.5 Hz, 2H), 7.69–7.67 (AA′ product was further extracted with dichloromethane (2 × 5 mL).
BB′, J = 8.5 Hz, 2H), 7.61–7.54 (m, 2H), 7.51 (dd, J = 8.5, 4.0 Hz, The combined organic layers were dried (Na2SO4) and filtered,
1H), 7.34–7.33 (AA′BB′, J = 8.5 Hz, 2H), 7.13–7.12 (AA′BB′, J = and the solvent was evaporated under reduced pressure. The
8.5 Hz, 2H), 6.74 (s, 1H), 3.37 (s, 3H). 13C NMR (125 MHz, crude product was purified by radial chromatography to yield
CDCl3): δ 151.2, 147.4, 141.0, 137.4, 136.6, 134.1, 133.6, 133.3, pure product 8.
132.3 (2C), 131.9 (2C), 131.3, 129.5, 128.8, 128.7 (2C), 127.5
1-{4-[5-(4-Nitrophenyl)-3-(5-nitroquinolin-8-yl)furan-2-yl]phenyl}
(2C), 126.6, 122.9, 121.7, 119.4, 118.9, 110.2, 110.1, 108.2, 33.8. ethan-1-one (8). Radial chromatography on silica gel (eluting
HRMS (ESI+): m/z calcd for C28H19N4 (M + H)+: 411.1604; with petroleum ether/dichloromethane; 1/1). Orange solid
found: 411.1597.
(87 mg, 45%); mp > 250 °C; Rf (light petroleum/EtOAc = 1/1)
8-[1-Methyl-3,5-bis(4-nitrophenyl)-1H-pyrrol-2-yl]quinoline (7ra). 0.68. FT-IR (ATR, neat): 2852, 1671, 1596, 1509, 1501, 1329,
1
Radial chromatography on silica gel (eluting with petroleum 1262, 1229, 850, 815, 704 cm−1. H NMR (500 MHz, CDCl3): δ
ether/EtOAc; 3/1). Orange solid (99 mg, 55%); mp
123–127 °C; Rf (light petroleum/EtOAc = 1/1) 0.43. FT-IR (ATR, (d, J = 8.0 Hz, 1H), 8.10–8.05 (m, 4H), 7.92–7.88 (m, 3H), 7.72
neat): 2925, 1589, 1505, 1330, 1105, 852, 725 cm−1 1H NMR (dd, J = 7.0, 4.0 Hz, 1H), 7.56–7.54 (AA′BB′, J = 9.0 Hz, 2H), 7.18
=
9.12 (dd, J = 9.0, 1.5 Hz, 1H), 8.98 (dd, J = 4.0, 1.5 Hz, 1H), 8.43
.
(500 MHz, CDCl3): δ 9.02 (dd, J = 4.0, 2.0 Hz, 1H), 8.33–8.31 (s, 1H), 2.66 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 197.2,
(m, 3H), 8.00 (dd, J = 8.0, 2.0 Hz, 1H), 7.94–7.92 (AA′BB′, J = 9.0 153.3, 151.6, 148.6, 146.6, 146.0, 145.6, 139.9, 136.4, 136.1,
Hz, 2H), 7.75–7.73 (AA′BB′, J = 9.0 Hz, 2H), 7.62 (dd, J = 7.0, 1.5 133.7, 132.4, 129.1 (3C), 126.1 (2C), 124.4 (2C), 124.3, 124.2
Hz, 1H), 7.59–7.56 (m, 1H), 7.53 (dd, J = 8.0, 4.0 Hz, 1H), (2C), 124.0 (2C), 121.9, 113.7, 26.6. HRMS (ESI+): m/z calcd for
7.18–7.17 (AA′BB′, J = 9.0 Hz, 2H), 6.84 (s, 1H), 3.41 (s, 3H). 13
C
C27H18N3O6 (M + H)+: 480.1190; found: 480.1187.
NMR (125 MHz, CDCl3): δ 151.3, 147.3, 146.3, 145.1, 143.1,
139.2, 136.7, 134.3, 134.0, 133.6, 131.1, 129.7, 128.9, 128.6
(2C), 127.4 (2C), 126.6, 124.0 (2C), 123.6 (2C), 122.7, 121.8,
110.9, 34.0. HRMS (ESI+): m/z calcd for C26H19N4O4 (M + H)+:
451.1401; found: 451.1394.
Procedure for the three-step one-pot transformation (Suzuki–
Miyaura coupling followed by C–H functionalization and
hydrogenation)
8-Bromo-5-nitroquinoline (2) (127 mg, 0.50 mmol), benzo[b]
furan-2-ylboronic acid (6f) (121 mg, 0.75 mmol), Pd(OAc)2
1-{4-[1-Methyl-5-(5-nitroquinolin-8-yl)-1H-pyrrol-2-yl]phenyl}
ethan-1-one (7u). Radial chromatography on silica gel (eluting (5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.05 mmol) and K2CO3
with petroleum ether/EtOAc; 5/1). Orange solid (68 mg, 47%); (207 mg, 1.5 mmol) were dissolved in a mixture of 1,4-dioxane
mp = 191–195 °C; Rf (light petroleum/EtOAc = 2/1) 0.35. FT-IR (1.6 mL) and water (0.4 mL). The reaction mixture was stirred
(ATR, neat): 2921, 1673, 1599, 1318, 1268, 789, 754, 732 cm−1
.
in a sealed glass tube at 100 °C for 24 h under an inert atmo-
1H NMR (500 MHz, CDCl3): δ 9.13–9.10 (m, 2H), 8.45 (d, J = 8.0 sphere. After allowing the mixture to cool to r.t. the glass tube
Hz, 1H), 8.05–8.04 (AA′BB′, J = 8.5 Hz, 2H), 7.87 (d, J = 8.0 Hz, was opened to which 1-bromo-4-nitrobenzene (81 mg,
1H), 7.70–7.66 (m, 3H), 6.60 (d, J = 4 Hz, 1H), 6.57 (d, J = 4 Hz, 0.40 mmol) and Pd(OAc)2 (5.6 mg, 0.025 mmol) were added.
1H), 3.51 (s, 3H), 2.65 (s, 3H). 13C NMR (125 MHz, CDCl3): δ The reaction mixture was again sealed and further stirred at
197.6, 151.3, 146.2, 144.5, 139.5, 137.7, 137.2, 135.3, 134.4, 120 °C for 24 h under an inert atmosphere. The mixture was
132.2, 129.4, 128.6 (2C), 128.5 (2C), 124.5, 123.8, 121.9, 113.1, allowed to cool to r.t. to which a flow of H2 (1 atm) was passed.
110.8, 35.1, 26.6. HRMS (ESI+): m/z calcd for C22H18N3O3 The reaction mixture was further stirred at r.t. for 24 h. After
(M + H)+: 372.1343; found: 372.1341.
the reaction was complete, water was added (5 mL) and the
product was further extracted with dichloromethane (2 ×
5 mL). The combined organic layers were dried (Na2SO4), fil-
tered and the solvent was evaporated under reduced pressure.
Procedure for the three-step one-pot transformation (Suzuki–
Miyaura coupling and two C–H functionalizations)
8-Bromo-5-nitroquinoline (2) (127 mg, 0.50 mmol), (furan-3-yl) The crude product was purified by radial chromatography to
boronic acid (6b) (84 mg, 0.75 mmol), Pd(OAc)2 (5.6 mg, yield pure product 9.
0.025 mmol), PPh3 (13.1 mg, 0.05 mmol) and K2CO3 (207 mg,
8-[3-(4-Aminophenyl)benzofuran-2-yl]quinolin-5-amine (9).
1.5 mmol) were dissolved in a mixture of 1,4-dioxane (1.6 mL) Radial chromatography on silica gel (eluting with petroleum
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ether/EtOAc; 1/1). Orange solid (98 mg, 70%); mp
202–204 °C; Rf (dichloromethane/methanol = 10/1) 0.38. FT-IR
=
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(ATR, neat): 3369, 3340, 1585, 1448, 1361, 1273, 1173, 1024,
1
823, 745 cm−1. H NMR (500 MHz, CDCl3): δ 8.88 (dd, J = 4.0,
1.5 Hz, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), 7.72 (d, J = 7.7 Hz,
1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.34 (dd,
J = 8.5, 4.0 Hz, 1H), 7.31–7.28 (m, 1H), 7.27–7.24 (m, 1H),
7.19–7.17 (AA′BB′, J = 8.5 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H),
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6.58–6.57 (AA′BB′, J = 8.5 Hz, 2H), 4.35 (s, 2H), 3.61 (s, 2H). 13
C
NMR (125 MHz, CDCl3): δ 154.8, 151.0, 150.6, 147.8, 144.9, 10 Y. Zhang, J. Gao, W. Li, H. Lee, B. Z. Lu and
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3780.
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