One-Pot Cross-Coupling/C-H Functionalization Reactions: Quinoline as a Substrate and Ligand through N-Pd Interaction

Article abstract of DOI:10.1021/acs.joc.9b03321

Herein, we report a one-pot process that marries mechanistically distinct, traditional cross-coupling reactions with C-H functionalization using the same precatalyst. The reactions proceed in yields of up to 95%, in air, and require no extraneous ligand.

Full text of DOI:10.1021/acs.joc.9b03321

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One-Pot Cross-Coupling/C−H Functionalization Reactions:
Quinoline as a Substrate and Ligand through N−Pd Interaction
Rachel M. Shanahan,⊥ Aobha Hickey,⊥ Lorraine M. Bateman, Mark E. Light, and Gerard P. McGlacken*
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ABSTRACT: Herein, we report a one-pot process that marries mechanistically
distinct, traditional cross-coupling reactions with C−H functionalization using the
same precatalyst. The reactions proceed in yields of up to 95%, in air, and require
no extraneous ligand. The reactions are thought to be facilitated by harnessing the
substrate quinoline as an N-ligand, and evidence of the palladium−quinoline
interaction is provided by 1H-15N HMBC NMR spectroscopy and X-ray
crystallographic structures. Application of the methodology is demonstrated by
the quick formation of fluorescent, π-extended frameworks.
functionalization of substrates with two different halogens
usually relies upon the marked difference in the rates of
oxidative addition (OA) at the C−X bonds. Using halogens of
the same type is considerably more difficult as significant rate
differences in the oxidation step (I vs Br or Br vs Cl) are not
easily harnessed.7 A limited number of one-pot reactions
combining C−H functionalization with a Suzuki−Miyaura
reaction have been reported.8 However, we are aware of very
few protocols that do not require perturbation of the reaction
setup by the addition of secondary reactants, reagents, or
catalysts subsequent to reaction initiation.9 In all cases, added
phosphine ligand is required. The use of phosphine ligands
adds significantly to the cost of any catalytic process; in fact,
they are often the most expensive component of a catalytic
system.10
This report describes a selection of one-pot tandem Suzuki−
Miyaura/direct arylation (SM/DA) and Mizoroki−Heck/
direct arylation (MH/DA) reactions with di- and tribromo-
quinolines. Once the reaction is initiated, no further
manipulation is required, and no subsequent addition of
solvents, reagents, reactants, or catalysts is needed. Overall, the
reaction proceeds using 2 mol % Pd(OAc)2, in air, and without
recourse to extraneous ligands. Through further development
to a one-pot Mizoroki−Heck/direct arylation protocol, π-
extended quinolines, with structural features of interest to
INTRODUCTION
■
The formation of multiple carbon−carbon bonds in a
telescoped, one-pot procedure is an efficient and environ-
mentally friendly approach to the construction of new chemical
entities.1 However, carrying out two or more chemical
reactions in a single vessel places significant demands on the
methodologies involved, specifically in terms of reagent,
catalyst, and substrate compatibility.2 Additionally, avoiding
secondary manipulation during a reaction is highly preferable if
the procedures are to be applied industrially.
Pyridine, quinoline, and furan moieties are prominent in
synthetic and naturally occurring pharmacologically active
compounds.3 In drugs, they represent the 2nd, 22nd, and 25th
most common ring systems, respectively.4 We recently
reported a palladium-catalyzed intramolecular direct arylation
(DA) protocol that gives a variety of benzofuro[3,2-
c]quinolines 2 from 4-(2-bromophenoxy)quinolines 1 in
excellent yields (Scheme 1).5
Chemoselectivity and regioselectivity proved to be very
predictable in these mono-halogenated systems. Conversely,
cross-coupling reactions involving substrates bearing more
than one halogen are far less predictable.2,6 The selective
Scheme 1. Intramolecular Direct Arylation of 1
Received: December 10, 2019
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© XXXX American Chemical Society
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A

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medicinal11 and materials12 chemists, were prepared. These
entities are challenging to synthesize by traditional, stepwise
cross-coupling techniques.13 We provide structural character-
ization of initially formed palladium−quinoline (Pd−Q)
complexes using cystallography, mass spectrometry, and
heteronuclear multiple bond correlation (HMBC) NMR
spectroscopy.
Table 1. Solvent and Base Screen for Tandem SM/DA
Reaction of 3a
RESULTS AND DISCUSSION
a
■
entry
1
base
solvent
NMP
1,4-dioxane
toluene
xylene
cyclohexanone
i-PrOAc
n-BuOAc
NMP
NMP
NMP
NMP
NMP
conv. (%)
yield (%)
Our initial aim was to test the chemoselectivity of 3a and
perhaps exploit entropic factors to carry out the intramolecular
DA reaction while leaving the bromide on the quinoline
backbone untouched. Using the reaction conditions that had
so efficiently furnished 2 from 1, no DA was observed (Scheme
2). We doubted that the bromine on the quinoline ring would
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
100
90
25
16
85
25
20
100
100
30
73 (75)
68
b
2
c
3
c
4
c
5
c
61
6
c
7
Scheme 2. Failed Intramolecular DA of Dibromoquinoline
3a
8
9
10
11
12
80
86 (83)
20
KOH
NaOH
NaOt-Bu
65
44
d
0
a
Yields determined by 1H NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard; values in
b
parentheses represent isolated yields. Reaction carried out at 125 °C.
c
d
Reaction carried out at 110 °C. Complete decomposition of 3a was
observed.
affect the electronics of the C-3 position to such an extent that
C−H functionalization would be prevented. Thus, we
rationalized that OA at the quinoline-Br was favored over
the phenoxy-Br. In the absence of a suitable coupling partner,
the OA product 3a′ was a catalytic dead end, with the
palladium trapped at a nonproductive site.
In an effort to liberate the palladium, phenylboronic acid was
introduced into the reaction mixture. Indeed, after optimiza-
tion, the Suzuki−Miyaura reaction occurred, along with the
direct arylation, giving 2-phenyl-benzofuro[3,2-c]quinoline 4a
in 83% isolated yield (Table 1).
A broad range of substituted phenylboronic acids underwent
one-pot tandem SM/DA coupling, allowing access to novel
benzofuroquinolines in good to excellent yields. Both electron-
releasing (4b and 4c) and electron-withdrawing (4d−4k)
groups were well tolerated. The chloride on 4f and 4l was
retained as a synthetic handle. Considering the prevalence of
the pyridine moiety in biologically active compounds,14 we
also applied the SM/DA reaction conditions to this substrate
and were pleased to furnish the benzofuropyridine 4m in good
yield. The Suzuki−Miyaura coupling was also conducive to
positioning the bromine at C-7 (4n−4r) (Figure 1a).
We were then keen to expand the scope of our one-pot
process to include Mizoroki−Heck transformations. Using
either tert-butyl acrylate or styrene derivatives, the one-pot
tandem MH/DA products were obtained in very good yields
(5a−5h) (Figure 1b). Both transformations also worked
efficiently when the second bromine was placed on the
phenoxy ring (6a−6c) (Figure 1c). Given the apparent
versatility of our methodology, a three-component tandem
process was devised using tribrominated substrates and two
equivalents of either coupling partner (7a−7c) (Figure 1d).
The structures of 4a, 4n, and 5b were confirmed by X-ray
diffraction analysis of single crystals (Figure 2 and see
Supporting Information S3−S6).
Incorporating heteroatomic substrates in cross-coupling
reactions usually necessitates the employment of an added
ligand and inert atmosphere,15 and in the reported C−H
functionalization of pyridines and quinolines,16 ancillary
ligands are also required. Considering that pyridines,17 and
indeed quinolines,18 possess the propensity to act as ligands for
palladium, we suspected that our methodology might be
underpinned by Pd−Q coordination. In order to determine
1
any Pd−Q interaction, we undertook H-15N HMBC NMR
spectroscopy. Inherent in this powerful technique are gradient-
enhanced pulse sequences, which allow for suppression of t1
noise facilitating the observation of the relatively weak long-
range 1H-15N correlations.19 Overall, the low natural
abundance and low gyromagnetic ratio are overcome. Using
this technique, structures 8a and 8b were elucidated. Initially,
0.5 equiv of Pd(OAc)21 was added to 1 and 3b in CDCl3
1
(Scheme 3), and the H, 13C, and H-15N HMBC NMR
spectra were recorded (see Supporting Information S14).
Complete consumption of both substrates was observed,
accompanied by upfield shifts in the 1H signals of the C-2, C-3,
and C-8 protons and a dramatic upfield shift in the 15N nucleus
resonance (for example, from 291.7 ppm 1 to 196.7 ppm 8a)
in the respective 1H-15N HMBC spectra (Figure 3 and
Supporting Information S14−S25). The significant shielding of
the nitrogen atom and the considerable accompanying shift in
both the C-2 and C-8 protons are indicative of direct Pd−N
coordination.20 Upon addition of Pd(OAc)2 to 3h, 1H and 13
C
NMR shifts analogous to those in 8a and 8b were observed.
1
Similar downfield shifts were also discerned in the H NMR
spectra of 8a in dioxane-d8 and ACN-d3 (Supporting
Information S16 and S20). Crystal structures for complexes
8a and 8c were obtained (Figure 4), and the compositions of
8a−8c were also verified by HRMS data (Supporting
Information S8−S13).
B
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Figure 2. Crystal structures of 4a, 4n, and 5b drawn at the 50%
probability level. Second molecule in the asymmetric unit of 4a
omitted for clarity (see Supporting Information S4 for further
information).
Scheme 3. Precatalyst Formation and Structure
Figure 3. 1H-15N HMBC NMR spectrum of 8a in CDCl3 at 300 K as
recorded at 600 MHz (1H) and 60 MHz (15N). All chemical shifts δ
reported in ppm.
Figure 1. One-pot tandem SM/DA and MH/DA substrate scope. All
a
yields are isolated. 2.2 equiv. of coupling partner employed in the
b
synthesis of 7a−7c. 5 mol % Pd(OAc)2 used for all styrene-based
derivatives.
We consider the Suzuki−Miyaura reaction to be the initial
transformation in the sequence (Supporting Information
Schemes S1 and S2), progressing via the typical Pd(II)/
Pd(0) mechanistic cycle. For the DA step, we postulate two
plausible mechanisms: first, OA at C−Br followed by C−H
activation via, for example, concerted metalation−deprotona-
Figure 4. Crystal structures of 8a and 8c drawn at the 50% probability
level. Disordered solvent (methanol) treated using solvent masking
techniques for structure 8c (see Supporting Information S4−S7 for
further information).
C
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Scheme 4. Preformed 8c/8a as Competent Precatalysts for the SM/DA Reaction
tion (CMD),21 and second, a Pd(II)/Pd(IV) route is also
plausible, as proposed by Yu and Morokuma.16a,22
the introduction of an electron releasing methoxy group (5d
and 5g) induced a hypsochromic shift relative to the parent
styrene compounds 5c and 5f. In contrast, the more
electronically poor quinoline frameworks (5e and 5h) were
blueshifted by a single nanometer. A significant bathochromic
shift and increased intensity are displayed in the emission
spectra for all compounds with respect to 2. The addition of
electron-poor/rich groups to our molecular framework gives
rise to tunable differences in emission intensity and wave-
length.
In summary, we report the occurrence of two mechanisti-
cally distinct reactions in one pot using the same precatalyst
and without a requisite for an added ligand. The reactions
work well in air, furnishing substituted benzofuroquinolines,
which represent an interesting molecular framework for
biological investigations. Direct evidence that the substrate
quinoline forms a precatalytic species with palladium is
provided, and excellent characterization data is furnished.
The π-extended products also display interesting and
potentially useful florescence properties.
Albeit undefined at this stage, we envisage these complexes
playing an important role as precatalysts, with the quinoline
aiding precatalyst-to-catalyst transformation, although it is
difficult to rule out an additional role of the quinoline in
preventing catalyst decomposition.23 Importantly, 8c was
deemed a competent precatalyst for the SM/DA reaction
(Scheme 4a). A further experiment using mono-bromo-Pd
complex 8a as the sole catalytic-source for the SM/DA
reaction yielded both 2 and 4a, proving that the Pd−Q
interaction is fluxional and ruling out a spectator-only role for
the quinoline ligands (analogous to phosphine ligands for
example) in the initially formed complexes 8a and 8b (Scheme
4b).24
Many small, conjugated organic molecules have the ability to
emit fluorescent light and can be exploited for a variety of
applications, such as in selective probes for ion detection12,25
and optoelectronic devices26 and as dyes or tags in
bioimaging.27 We were intrigued to investigate if our π-
extended MH/DA products displayed any useful photophysical
characteristics. Thus, UV−Visible absorption data for the
styrene-functionalized compounds 2, 5c−5h, 6c, and 7c was
obtained, and their fluorescent properties were investigated.
The standard benzofuro[3,2-c]quinoline framework 2 is given
for comparison (Table 2).
EXPERIMENTAL SECTION
■
Materials and Methods. Solvents and reagents were used as
obtained from commercial sources and without purification.
Melting points were measured in a Thomas Hoover Capillary
Melting Point apparatus.
Infrared spectra were measured on a Perkin-Elmer FT-IR
spectrometer as thin films in dichloromethane (DCM).
Column chromatography was carried out using 60 Å (35−70 μm)
silica. Thin-layer chromatography (TLC) was carried out on
precoated silica gel plates (Merck 60 PF254). The developed plates
were visualized under UV light.
High-resolution precise mass spectra (HRMS) were recorded on a
Waters LCT Premier Tof LC-MS instrument in University College
Cork. Samples were run in electrospray ionization (ESI) mode using
50% acetonitrile/water containing 0.1% formic acid as an eluent;
samples were made up at a concentration of ca. 1 mg mL−1. HRMS of
metal-containing complexes were recorded on a Bruker compact
TOF-MS in the University of York. Samples were run in electrospray
ionization (ESI) mode using 50% MeOH/water as eluent; samples
were made up at a concentration of ca. 1 mg mL−1. Acquisitions were
internally calibrated using sodium formate clusters.
All compounds exhibit their maximum absorption band
(λmax) in the UV or near-UV region and yield large molar
absorption coefficients (ε) in the range of 104 dm3 mol−1 cm−1.
The addition of further auxochromes to the substituted
frameworks resulted in notable shifts in λmax. For example,
Table 2. UV−Vis Data, Fluorescence Emission (em.) Data,
and Molar Absorption Coefficients (ε) for Compounds 2,
5c−5h, 6c, and 7c (See Supporting Information S125−S133
for More Information)
a
compd
abs. λmax (nm)
em. λem (nm)
ε
(dm3 mol−1 cm−1
)
2
257
301
259
300
337
260
336
258
342
353
389
416
388
387
421
386
382
346
63,300
45,188
38,338
42,000
38,500
31,700
43,638
36,538
51,438
5c
5d
5e
5f
5g
5h
6c
7c
Nuclear magnetic resonance (NMR) samples were run in
deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide
((CD3)2SO), deuterated dioxane (C4D8O2), or deuterated acetoni-
1
1
trile (C2D3N) as specified. H NMR (600 MHz) and H NMR (300
MHz) spectra were recorded on Bruker Avance III 600 and Bruker
Avance III 300 NMR spectrometers, respectively, in proton-coupled
mode using tetramethysilane (TMS) as the internal standard. 13C
NMR (150 MHz), 13C NMR (100 MHz), and 13C NMR (75 MHz)
spectra were recorded on Bruker Avance III 600, Bruker Avance 400,
and Bruker Avance III 300 NMR spectrometers, respectively, in
a
ε calculated at 8 × 10−6 mol dm−3.
D
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proton-decoupled mode at 300 K using TMS as the internal standard.
19F NMR (282 MHz) spectra were recorded on a Bruker Avance III
general procedure for the synthesis of 4-phenoxyquinolines above to
give the title product as a pale yellow solid; yield: 1.397 g (92%); m.p.
73−74 °C; IR (NaCl): ν 3064, 1561, 1468, 1301, 1220, 657 cm−1; 1H
NMR (300 MHz, CDCl3) δ: 6.41 (d, J = 5.2 Hz, 1H), 7.19−7.30 (m,
2H), 7.39−7.48 (m, 1H), 7.66−7.76 (m, 2H), 8.25−8.33 (m, 2H),
8.66 (d, J = 5.2 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ:
103.9, 116.3, 119.7, 123.3, 123.5, 124.6, 127.6, 129.3, 129.8, 131.4,
134.4, 150.5, 150.8, 152.1, 160.8 ppm; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H10Br2NO 377.9129; found: 377.9119.
300 NMR spectrometer in proton-decoupled mode at 300 K. 1H-15N
HMBC spectra were recorded on a Bruker Avance III 600 NMR
spectrometer [600 MHz (1H) and 60 MHz (15N)] equipped with
Bruker BBFO cryoprobe. All spectra recorded at 300 K and
referenced externally to nitromethane at 380.2 ppm, and the value
of which was uncorrected. 1H-15N HMBC spectra were acquired using
the Bruker HMBC pulse program (2D H-1/X correlation via
heteronuclear zero and double quantum coherence optimized on
long-range couplings) with four scans and a spectral width of 600−
650 ppm. All spectra were run at University College Cork. Chemical
shifts (δ) are expressed as parts per million (ppm), positive shift being
downfield from TMS; coupling constants (J) are expressed in hertz
(Hz). Splitting patterns in 1H NMR spectra are designated as follows:
s (singlet), bs (broad singlet), d (doublet), dd (doublet of doublets),
ddd (doublet of doublets of doublets), t (triplet), td (triplet of
doublets), q (quartet), quin (quintet), and m (multiplet).
6-Bromo-4-(2-bromo-4-chlorophenoxy)quinoline (3c). 6-Bromo-
4-chloroquinoline (0.500 g, 2.06 mmol), 2-bromo-4-chlorophenol
(2.140 g, 10.31 mmol), and NaOH (0.126 g, 3.14 mmol) were
reacted according to the general procedure for the synthesis of 4-
phenoxyquinolines above to give the title product as a pale pink solid;
yield: 531 mg (77%); m.p. 157−159 °C; IR (NaCl): ν 3392, 1590,
1
1467, 1349, 1256, 729, 667 cm−1; H NMR (300 MHz, CDCl3) δ:
6.41 (d, J = 5.1 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6,
2.5 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 9.0, 2.2 Hz, 1H),
7.98 (d, J = 9.0 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 5.1 Hz,
1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 104.1, 117.0, 120.5,
122.0, 124.0, 124.2, 129.4, 131.0, 132.4, 133.9, 134.0, 148.4, 149.6,
151.3, 159.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H9Br2ClNO 411.8739; found: 411.8730.
Single-crystal X-ray analysis was performed on a Rigaku AFC12
FRE-HF diffractometer equipped with an Oxford Cryosystems low-
temperature device. The crystals were kept at a steady T = 100(2) K
during data collection. The structures were solved with the ShelXT28
structure solution program using the Intrinsic Phasing solution
method and by using Olex229 as the graphical interface. The models
were refined with version 2016/6 of ShelXL28 using least-squares
minimization. Cell parameters were retrieved and refined using the
CrysAlisPro (Rigaku, V1.171.40.37a, 2019). All nonhydrogen atoms
were refined anisotropically. Hydrogen atom positions were calculated
geometrically and refined using the riding model. Further information
is available in the Supporting Information.
UV−Visible absorption was measured on a Thermo Scientific
Evolution 60S UV−Visible spectrophotometer. All solutions were
made up in DCM, and measurements were performed in high-
precision quartz cells of 10 mm in path length. A baseline in DCM
was recorded by an internal reference detector. Molar absorption
values were calculated using Beer’s law at a concentration of 8 × 10−6
mol dm−3. Fluorescence intensities were measured on a PerkinElmer
Fluorescence Spectrometer LS 55. All solutions were made up in
DCM, and measurements were performed in high-precision quartz
cells of 10 × 10 mm in path length. Spectra were recorded in the
range of 200−700 nm, and compounds were excited at 257 nm.
General Procedure for the Synthesis of 4-Phenoxyquino-
line Substrates. A mixture of the 4-chloroquinoline substrate (1
equiv), the phenol (5 equiv), and NaOH (crushed pellets) (1.5 equiv)
was stirred at 120 °C in an aluminum heating mantle until the
reaction was complete (2−6 h) as evidenced by TLC (Hex/EtOAc
8:2). The cooled reaction mixture was diluted with 10% aqueous
NaOH (5 mL) and stirred at room temperature for 1 h. The aqueous
phase was extracted with DCM (3 × 20 mL). The combined organic
layers were washed with 6 M NaOH (3 × 10 mL), water (10 mL),
and brine (10 mL), dried over MgSO4, filtered, and concentrated in
vacuo. The crude mixture was purified by column chromatography
over silica gel using Hex/EtOAc (8:2) as an eluent unless otherwise
specified.
4-(2,6-Dibromophenoxy)pyridine (3d). A neat mixture of 4-
chloropyridine (0.250 g, 1.66 mmol) and 2,6-dibromophenol (0.630
g, 2.50 mmol) was stirred at 120 °C in an aluminum heating mantle
until the reaction was complete (16 h) as evidenced by TLC (Hex/
EtOAc 8:2). The cooled reaction mixture was diluted with 10%
aqueous NaOH (5 mL) and stirred at room temperature for 1 h. The
aqueous phase was extracted with DCM (3 × 20 mL). The combined
organic layers were washed with 6 M NaOH (3 × 10 mL), water (10
mL), and brine (10 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture was purified by
recrystallization from cyclohexane to give the title product as an off-
white solid; yield: 365 mg (66%); m.p. 91−93 °C; IR (NaCl): ν 3393,
1
1590, 1434, 1261, 1200, 665 cm−1; H NMR (300 MHz, CDCl3) δ:
6.75 (d, J = 5.0 Hz, 2H), 7.07 (t, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.1,
1.9 Hz, 2H), 8.49 (d, J = 5.2 Hz, 2H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 110.8, 118.3, 128.3, 133.1, 147.7, 151.5, 162.5 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H8Br2NO 327.8973;
found: 327.8961.
4-(2,4-Dibromophenoxy)quinoline (3e). 4-Chloroquinoline
(0.260 g, 1.60 mmol), 2,4-dibromophenol (2.00 g, 7.90 mmol), and
NaOH (0.095 g, 2.40 mmol) were reacted according to the general
procedure for the synthesis of 4-phenoxyquinolines above to give the
title product as a pale yellow solid; yield: 517 mg (85%); m.p. 125−
1
126 °C; IR (NaCl): ν 3394, 1596, 1464, 1305, 1224, 667 cm−1; H
NMR (300 MHz, CDCl3) δ: 6.43 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 8.6
Hz, 1H), 7.50−7.68 (m, 2H), 7.79 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H),
7.88 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 8.4,
0.9 Hz, 1H), 8.70 (d, J = 5.1 Hz, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 103.8, 117.4, 119.3, 120.9, 121.8, 124.3, 126.5, 129.2,
130.4, 132.3, 136.6, 149.8, 150.5, 151.0, 160.3 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H10Br2NO 377.9129; found:
377.9114.
6-Bromo-4-(2,4-dibromophenoxy)quinoline (3f). 6-Bromo-4-
chloroquinoline (0.240 g, 0.99 mmol), 2,4-dibromophenol (1.247 g,
4.95 mmol), and NaOH (0.059 g, 1.5 mmol) were reacted according
to the general procedure for the synthesis of 4-phenoxyquinolines
above to give the title product as a pale yellow solid; yield: 268 mg
(59%); m.p. 162−163 °C; IR (NaCl): ν 3370, 1590, 1449, 1349,
1255, 665 cm−1; 1H NMR (300 MHz, CDCl3) δ: 6.42 (d, J = 5.1 Hz,
1H), 7.12 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.6, 2.3 Hz, 1H), 7.80−
7.91 (m, 2H), 7.98 (d, J = 9.0 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.68
(d, J = 5.1 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 104.2,
117.4, 119.7, 120.5, 122.0, 124.2, 124.4, 131.0, 132.4, 133.9, 136.7,
148.4, 150.1, 151.3, 159.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H9Br3NO 455.8234; found: 455.8233.
6-Bromo-4-(2-bromophenoxy)quinoline (3a). 6-Bromo-4-chloro-
quinoline (0.970 g, 4.0 mmol), 2-bromophenol (2.32 mL, 20 mmol),
and NaOH (0.240 g, 6.0 mmol) were reacted according to the general
procedure for the synthesis of 4-phenoxyquinolines above to give the
title product as a pale yellow solid; yield: 1.406 g (93%); m.p. 97−98
°C; IR (NaCl): ν 3399, 1590, 1491, 1350, 1221, 665 cm−1; 1H NMR
(300 MHz, CDCl3) δ: 6.41 (d, J = 5.2 Hz, 1H), 7.19−7.28 (m, 2H),
7.39−7.47 (m, 1H), 7.73 (dd, J = 8.3, 1.5 Hz, 1H), 7.84 (dd, J = 9.0,
2.2 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.67
(d, J = 5.2 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 104.2,
116.4, 120.3, 122.2, 123.3, 124.3, 127.6, 129.3, 130.9, 133.7, 134.4,
148.4, 150.8, 151.4, 159.8 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H10Br2NO 377.9129; found: 377.9132.
7-Bromo-4-(2-bromophenoxy)quinoline (3b). 7-Bromo-4-chloro-
quinoline (0.970 g, 4.0 mmol), 2-bromophenol (2.32 mL, 20.0
mmol), and NaOH (0.240 g, 6.0 mmol) were reacted according to the
7-Bromo-4-(2,4-dibromophenoxy)quinoline (3g). 7-Bromo-4-
chloroquinoline (0.243 g, 1.0 mmol), 2,4-dibromophenol (1.26 g,
E
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5.0 mmol), and NaOH (0.06 g, 1.5 mmol) were reacted according to
the general procedure for the synthesis of 4-phenoxyquinolines above
to give the title product as a white solid; yield: 398 mg (87%); m.p.
140−142 °C; IR (NaCl) ν 3583, 1615, 1559, 1302, 1096, 666 cm−1;
1H NMR (300 MHz, CDCl3) δ: 6.42 (d, J = 5.2 Hz, 1H), 7.13 (d, J =
8.6 Hz, 1H), 7.56 (dd, J = 8.6, 2.3 Hz, 1H), 7.70 (dd, J = 8.9, 1.9 Hz,
1H), 7.88 (d, J = 2.3 Hz, 1H), 8.18−8.36 (m, 2H), 8.68 (d, J = 5.2
Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 103.9, 117.4,
119.6, 119.7, 123.3, 124.4, 124.7, 130.0, 131.5, 132.4, 136.7, 150.2,
150.5, 152.1, 160.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H9Br3NO 455.8229; found: 455.8233.
(300 MHz, CDCl3) δ: 2.45 (s, 3H), 7.35 (d, J = 7.9 Hz, 2H), 7.44−
7.62 (m, 2H), 7.69−7.82 (m, 3H), 8.02−8.16 (m, 2H), 8.33 (d, J =
8.8 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 9.49 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 21.2, 112.1, 116.5, 117.4, 118.0, 120.7,
122.7, 124.1, 127.27, 127.34, 128.8, 129.8, 130.2, 137.2, 137.9, 139.6,
144.0, 146.6, 156.0, 157.6 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H16NO 310.1232; found: 310.1222.
2-(4-Methoxyphenyl)benzofuro[3,2-c]quinoline (4c). A mixture
of substrate 3a (0.150 g, 0.396 mmol), 4-methoxyphenylboronic acid
(0.066 g, 0.435 mmol), Pd(OAc)2 (4.5 mg, 5 mol %), and anhydrous
K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot SM/DA
procedure above to give the title product as a white solid; yield: 84 mg
(65%); m.p. 189−191 °C; IR (NaCl): ν 3320, 1505, 1460, 1359,
4-Phenoxyquinoline (3h).30 4-Chloroquinoline (0.164 g, 1.0
mmol), phenol (0.471 g, 5.0 mmol), and NaOH (0.06 g, 1.5
mmol) were reacted according to the general procedure for the
synthesis of 4-phenoxyquinolines above to give the title product as a
yellow oil; yield: 192 mg (87%); 1H NMR (300 MHz, CDCl3) δ: 6.54
(d, J = 5.2 Hz, 1H), 7.13−7.22 (m, 2H), 7.23−7.33 (m, 1H), 7.39−
7.50 (m, 2H), 7.56 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.74 (ddd, J = 8.5,
6.9, 1.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.36 (dd, J = 8.4, 1.1 Hz,
1H), 8.66 (d, J = 5.1 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δ: 104.4, 121.1, 121.5, 121.8, 125.6, 126.1, 129.1, 130.1, 130.3, 149.8,
151.1, 154.4, 161.9 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H12NO 222.0913; found: 222.0913.
6-Bromo-4-phenoxyquinoline (3i). 6-Bromo-4-chloroquinoline
(0.500 g, 2.1 mmol), phenol (0.970 g, 10.31 mmol), and NaOH
(0.126 g, 3.14 mmol) were reacted according to the general procedure
for the synthesis of 4-phenoxyquinolines above to give the title
product as a pale yellow solid; yield: 517 mg (83%); m.p. 84−86 °C;
IR (NaCl): ν 3401, 1561, 1487, 1351, 1213, 667 cm−1; 1H NMR (300
MHz, CDCl3) δ: 6.54 (d, J = 5.2 Hz, 1H), 7.13−7.22 (m, 2H), 7.25−
7.36 (m, 1H), 7.41−7.53 (m, 2H), 7.80 (dd, J = 9.0, 2.2 Hz, 1H), 7.95
(d, J = 9.0 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.65 (d, J = 5.2 Hz, 1H)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 104.7, 120.2, 121.1, 122.6,
124.3, 125.9, 130.4, 130.9, 133.6, 148.3, 151.5, 154.0, 161.0 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H11BrNO 300.0024;
found: 300.0013.
1
1246, 1190 cm−1; H NMR (300 MHz, CDCl3) δ: 3.90 (s, 3H),
7.01−7.12 (m, 2H), 7.43−7.60 (m, 2H), 7.71−7.81 (m, 3H), 8.01
(dd, J = 8.8, 2.1 Hz, 1H), 8.10 (dd, J = 7.6, 0.9 Hz, 1H), 8.30 (d, J =
8.8 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 9.46 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 55.4, 112.1, 114.5, 116.5, 117.4, 117.5,
120.6, 122.7, 124.1, 127.2, 128.56, 128.61, 130.2, 132.6, 139.3, 143.9,
146.4, 156.0, 157.5, 159.7 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H16NO2 326.1181; found: 326.1185.
2-(4-(Trifluoromethoxy)phenyl)benzofuro[3,2-c]quinoline (4d). A
mixture of substrate 3a (0.150 g, 0.396 mmol), (4-(trifluoromethoxy)-
phenyl)boronic acid (0.090 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2
mol %), and anhydrous K2CO3 (0.109 g, 0.79 mmol) in anhydrous
NMP (0.6 mL, 1.5 mL mmol−1) was reacted according to the general
one-pot SM/DA procedure above to give the title product as a yellow
solid; yield: 105 mg (70%); m.p. 148−150 °C; IR (NaCl): ν 3583,
1504, 1459, 1283, 1210, 1191, 1165 cm−1; 1H NMR (300 MHz,
CDCl3) δ: 7.37 (dd, J = 8.8, 0.9 Hz, 2H), 7.43−7.62 (m, 2H), 7.72−
7.86 (m, 3H), 7.97 (dd, J = 8.8, 2.1 Hz, 1H), 8.09 (dd, J = 7.6, 0.8 Hz,
1H), 8.31 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 9.47 (s, 1H)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 112.1, 116.8, 117.4, 118.6,
1
120.5 (q, J(C,F) = 257 Hz), 120.7, 121.4, 122.6, 124.2, 127.4, 128.5,
3
128.9, 130.5, 138.3, 138.9, 144.5, 146.7, 149.2 (q, J(C,F) = 2 Hz),
General Procedure for Palladium-Catalyzed One-Pot Suzu-
ki−Miyaura and Intramolecular Direct Arylation Reactions. A
mixture of the 4-(2-bromophenoxy)quinoline substrate (1 equiv),
PhB(OH)2 (1.1 equiv), Pd(OAc)2 (2 mol %), and anhydrous K2CO3
(2 equiv) in anhydrous NMP (1.5 mL mmol−1) was stirred at 135 °C
in a sealed reaction tube in an aluminum multireaction heating mantle
156.0, 157.5 ppm; 19F{1H} NMR (282 MHz, CDCl3) δ: −58 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H13F3NO2 380.0898;
found: 380.0889.
2-(4-Fluorophenyl)benzofuro[3,2-c]quinoline (4e). A mixture of
substrate 3a (0.150 g, 0.396 mmol), 4-fluorophenylboronic acid
(0.061 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous
K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot SM/DA
procedure above to give the title product as a pale yellow solid; yield:
95 mg (77%); m.p. 185−186 °C; IR (NaCl): ν 3391, 1561, 1460,
1
until the reaction was complete as evidenced by H NMR analysis.
The cooled reaction mixture was diluted with DCM, filtered through
a short plug of Celite, and concentrated in vacuo. The crude mixture
was purified by column chromatography over silica gel using DCM/
EtOAc (99:1−95:5) as an eluent unless otherwise specified.
1
1334, 1192, 1123 cm−1; H NMR (300 MHz, CDCl3) δ: 7.16−7.29
2-Phenylbenzofuro[3,2-c]quinoline (4a). A mixture of substrate
3a (0.100 g, 0.26 mmol), phenylboronic acid (0.035 g, 0.29 mmol),
Pd(OAc)2 (1.2 mg, 2 mol %), and anhydrous K2CO3 (0.073 g, 0.53
mmol) in anhydrous NMP (0.4 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above to give the
title product as a pale yellow solid; X-ray quality crystals were
obtained via vapor diffusion from a saturated solution of toluene in
hexane, the CCDC number is 1967876; yield: 63 mg (83%); m.p.
(m, 2H), 7.46−7.62 (m, 2H), 7.72−7.83 (m, 3H), 8.00 (dd, J = 8.8,
2.1 Hz, 1H), 8.13 (dd, J = 7.2, 1.3 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H),
8.57 (d, J = 2.0 Hz, 1H), 9.50 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
2
CDCl3) δ: 112.1, 115.9 (d, J(C,F) = 22 Hz), 116.7, 117.4, 118.2,
3
120.7, 122.7, 124.1, 127.3, 128.6, 129.1 (d, J(C,F) = 8 Hz), 130.4,
1
136.2, 138.7, 144.3, 146.6, 156.0, 157.5, 162.9 (d, J(C,F) = 247 Hz)
ppm; 19F{1H} NMR (282 MHz, CDCl3) δ: −115 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H13FNO 314.0981; found:
314.0971.
1
169−171 °C; IR (NaCl): ν 3450, 1559, 1460, 1359, 1193 cm−1; H
NMR (300 MHz, CDCl3) δ: 7.39−7.61 (m, 5H), 7.74−7.87 (m, 3H),
8.02−8.15 (m, 2H), 8.33 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 1.7 Hz,
1H), 9.49 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 112.1,
116.6, 117.3, 118.4, 120.6, 122.7, 124.1, 127.3, 127.5, 127.9, 128.8,
129.0, 130.2, 139.7, 140.1, 144.2, 146.7, 156.0, 157.6 ppm; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H14NO 296.1075; found:
296.1062.
2-(4-Chlorophenyl)benzofuro[3,2-c]quinoline (4f). A mixture of
substrate 3a (0.150 g, 0.396 mmol), 4-chlorophenylboronic acid
(0.068 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous
K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot SM/DA
procedure above to give the title product as a pale yellow solid; yield:
106 mg (81%); m.p. 191−192 °C; IR (NaCl): ν 3389, 1556, 1458,
2-(p-Tolyl)benzofuro[3,2-c]quinoline (4b). A mixture of substrate
3a (0.150 g, 0.396 mmol), o-tolylboronic acid (0.059 g, 0.435 mmol),
Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous K2CO3 (0.109 g, 0.79
mmol) in anhydrous NMP (0.6 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above to give the
title product as a white solid; yield: 89 mg (72%); m.p. 183−185 °C;
1
1356, 1191, 821 cm−1; H NMR (300 MHz, CDCl3) δ: 7.38−7.57
(m, 4H), 7.61−7.75 (m, 3H), 7.89 (dd, J = 8.8, 2.1 Hz, 1H), 8.02 (dd,
J = 7.6, 0.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 2.0 Hz,
1H), 9.39 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 112.1,
116.7, 117.3, 118.2, 120.7, 122.6, 124.1, 127.3, 128.3, 128.6, 129.1,
130.4, 134.1, 138.3, 138.5, 144.4, 146.7, 155.9, 157.4 ppm; HRMS
1
IR (NaCl): ν 3583, 3401, 1505, 1460, 1358, 1190 cm−1; H NMR
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(ESI-TOF) m/z: [M + H]+ calcd for C21H13ClNO 330.0680; found:
330.0676.
was reacted according to the general one-pot SM/DA procedure
above to give the title product as a yellow solid; yield: 69 mg (51%);
m.p. 227−228 °C; IR (NaCl): ν 3392, 1529, 1460, 1348, 1321, 1191
cm−1; 1H NMR (300 MHz, CDCl3) δ: 7.47−7.64 (m, 2H), 7.72 (t, J
= 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.8, 2.2 Hz,
1H), 8.10−8.19 (m, 2H), 8.30 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.40 (d,
J = 8.8 Hz, 1H), 8.65−8.73 (m, 2H), 9.55 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 112.2, 117.0, 117.4, 119.1, 120.8, 122.3,
122.5, 122.6, 124.3, 127.6, 128.2, 130.0, 131.0, 133.3, 137.1, 141.9,
145.1, 147.0, 148.9, 156.1, 157.5 ppm; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C21H13N2O3: 341.0921; found: 341.0919.
2-(4-(Trifluoromethyl)phenyl)benzofuro[3,2-c]quinoline (4g). A
mixture of substrate 3a (0.150 g, 0.396 mmol), (4-(trifluoromethyl)-
phenyl)boronic acid (0.083 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2
mol %), and anhydrous K2CO3 (0.109 g, 0.79 mmol) in anhydrous
NMP (0.6 mL, 1.5 mL mmol−1) was reacted according to the general
one-pot SM/DA procedure above to give the title product as a pale
yellow solid; yield: 114 mg (80%); m.p. 194−195 °C; IR (NaCl): ν
3384, 1614, 1460, 1331, 1189, 1116 cm−1; 1H NMR (300 MHz,
CDCl3) δ: 7.46−7.63 (m, 2H), 7.74−7.85 (m, 3H), 7.93 (d, J = 8.2
Hz, 2H), 8.04 (dd, J = 8.8, 2.1 Hz, 1H), 8.13 (d, J = 7.4 Hz, 1H), 8.37
(d, J = 8.8 Hz, 1H), 8.65 (d, J = 1.9 Hz, 1H), 9.53 (s, 1H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δ: 112.1, 116.8, 117.3, 119.0, 120.7,
8-Chloro-2-phenylbenzofuro[3,2-c]quinoline (4l). A mixture of
substrate 3c (0.200 g, 0.60 mmol), phenylboronic acid (0.080 g, 0.658
mmol), Pd(OAc)2 (2.7 mg, 2 mol %), and anhydrous K2CO3 (0.165
g, 1.20 mmol) in anhydrous NMP (0.9 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot SM/DA procedure above to
give the title product as a pale yellow solid; yield: 118 mg (60%); m.p.
1
3
122.6, 124.22, 124.23 (q, J(C,F) = 270 Hz), 125.9 (q, J(C,F) = 4 Hz),
2
127.5, 127.7, 128.4, 130.0 (q, J(C,F) = 33 Hz), 130.6, 138.1, 143.6,
144.8, 146.9, 156.0, 157.5 ppm; 19F{1H} NMR (282 MHz, CDCl3) δ:
−62 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H13F3NO
364.0949; found: 364.0938.
1
213−214 °C; IR (NaCl): ν 3583, 1461, 1359, 1192, 665 cm−1; H
NMR (300 MHz, CDCl3) δ: 7.38−7.60 (m, 4H), 7.66 (d, J = 8.8 Hz,
1H), 7.75−7.87 (m, 2H), 7.99−8.12 (m, 2H), 8.31 (d, J = 8.8 Hz,
1H), 8.55 (d, J = 1.8 Hz, 1H), 9.41 (s, 1H) ppm; 13C{1H} NMR (75
MHz, CDCl3) δ: 113.1, 115.8, 117.2, 118.4, 120.5, 124.2, 127.4,
127.5, 128.1, 129.1, 129.3, 129.9, 130.4, 140.0, 140.1, 144.0, 147.0,
154.3, 158.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C21H13ClNO 330.0681; found: 330.0684.
2-(3-(Trifluoromethyl)phenyl)benzofuro[3,2-c]quinoline (4h). A
mixture of substrate 3a (0.150 g, 0.396 mmol), (3-(trifluoromethyl)-
phenyl)boronic acid (0.083 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2
mol %), and anhydrous K2CO3 (0.109 g, 0.79 mmol) in anhydrous
NMP (0.6 mL, 1.5 mL mmol−1) was reacted according to the general
one-pot SM/DA procedure above to give the title product as a pale
yellow solid; yield: 104 mg (72%); m.p. 171−173 °C; IR (NaCl): ν
3391, 1561, 1446, 1334, 1166, 1123 cm−1; 1H NMR (300 MHz,
CDCl3) δ: 7.45−7.73 (m, 4H), 7.79 (d, J = 7.9 Hz, 1H), 7.95−8.09
(m, 3H), 8.13 (dd, J = 7.6, 0.8 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.63
(d, J = 2.0 Hz, 1H), 9.52 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 112.1, 116.8, 117.3, 118.7, 120.7, 122.6, 124.19, 124.20 (q,
6-Phenylbenzofuro[3,2-c]pyridine (4m). A mixture of substrate 3d
(0.150 g, 0.456 mmol), phenylboronic acid (0.061 g, 0.50 mmol),
Pd(OAc)2 (2.0 mg, 2 mol %), and anhydrous K2CO3 (0.126 g, 0.912
mmol) in anhydrous NMP (0.7 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above and
purified via column chromatography using 100% Et2O as an eluent to
give the title product as a pale yellow solid; yield: 77 mg (69%); m.p.
66−68 °C; IR (NaCl): ν 3402, 3032, 1577, 1450, 1332, 1168 cm−1;
1H NMR (300 MHz, CDCl3) δ: 7.35−7.63 (m, 5H), 7.67 (dd, J = 7.6,
1.3 Hz, 1H), 7.83−7.92 (m, 2H), 8.01 (dd, J = 7.7, 1.3 Hz, 1H), 8.67
(d, J = 5.7 Hz, 1H), 9.30 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 107.6, 120.1, 121.6, 122.4, 124.4, 126.4, 128.07, 128.13,
128.77, 128.80, 135.8, 143.7, 147.5, 153.1, 160.9 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H12NO 246.0913; found:
246.0914. Note: Here, a second Suzuki−Miyaura reaction occurred in
competition with the direct arylation. These products were separable
by careful column chromatography.
3
3
1J(C,F) = 273 Hz), 124.3 (q, J(C,F) = 4 Hz), 124.6 (q, J(C,F) = 4 Hz),
2
127.5, 128.4, 129.5, 130.6, 130.7, 131.5 (q, J(C,F) = 32 Hz), 138.1,
140.9, 144.7, 146.8, 156.0, 157.5 ppm; 19F{1H} NMR (282 MHz,
CDCl3) δ: −62 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H13F3NO 364.0944; found: 364.0947.
Ethyl 4-(Benzofuro[3,2-c]quinolin-2-yl)benzoate (4i). A mixture
of substrate 3a (0.150 g, 0.396 mmol), 4-ethoxycarbonylphenylbor-
onic acid (0.084 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and
anhydrous K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL,
1.5 mL mmol−1) was reacted according to the general one-pot SM/
DA procedure above to give the title product as a beige solid; yield:
105 mg (70%); m.p. 160−161 °C; IR (NaCl): ν 2922, 1715, 1607,
3-Phenylbenzofuro[3,2-c]quinoline (4n). A mixture of substrate
3b (0.200 g, 0.528 mmol), phenylboronic acid (0.071 g, 0.58 mmol),
Pd(OAc)2 (2.4 mg, 2 mol %), and anhydrous K2CO3 (0.146 g, 1.06
mmol) in anhydrous NMP (0.8 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above to give the
title product as a pale yellow solid; X-ray quality crystals were
obtained via vapor diffusion from a saturated solution of toluene in
hexane, the CCDC number is 1967484; yield: 146 mg (95%); m.p.
1
1460, 1357, 1278, 1190 cm−1; H NMR (300 MHz, CDCl3) δ: 1.45
(t, J = 7.1 Hz, 3H), 4.44 (q, J = 7.1 Hz, 2H), 7.43−7.63 (m, 2H), 7.79
(d, J = 7.9 Hz, 1H), 7.84−7.95 (m, 2H), 8.02−8.28 (m, 4H), 8.36 (d,
J = 8.8 Hz, 1H), 8.67 (d, J = 1.7 Hz, 1H), 9.52 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 14.4, 61.1, 112.1, 116.7, 117.2, 118.8,
120.7, 122.5, 124.1, 127.3, 127.4, 128.8, 129.8, 130.2, 130.5, 138.3,
144.2, 144.6, 146.9, 155.9, 157.4, 166.4 ppm; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C24H18NO3: 368.1281; found: 368.1282.
(4-(Benzofuro[3,2-c]quinolin-2-yl)phenyl)(phenyl)methanone
(4j). A mixture of substrate 3a (0.150 g, 0.396 mmol), (4-
benzoylphenyl)boronic acid (0.098 g, 0.435 mmol), Pd(OAc)2 (1.8
mg, 2 mol %), and anhydrous K2CO3 (0.109 g, 0.79 mmol) in
anhydrous NMP (0.6 mL, 1.5 mL mmol−1) was reacted according to
the general one-pot SM/DA procedure above to give the title product
as a pale yellow solid; yield: 94 mg (59%); m.p. 184−187 °C; IR
1
172−173 °C; IR (NaCl): ν 3275, 1559, 1452, 1379, 1188 cm−1; H
NMR (300 MHz, CDCl3) δ: 7.37−7.64 (m, 5H), 7.72−7.88 (m, 3H),
7.98 (dd, J = 8.5, 1.7 Hz, 1H), 8.12 (dd, J = 7.5, 1.0 Hz, 1H), 8.42−
8.59 (m, 2H), 9.54 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ:
112.2, 116.1, 116.4, 120.6, 121.3, 122.8, 124.1, 126.6, 127.3, 127.5,
127.6, 128.0, 129.1, 140.2, 142.2, 144.9, 147.8, 156.1, 157.5 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H14NO 296.1070;
found: 296.1072.
1
(NaCl): ν 3401, 1652, 1602, 1460, 1357, 1190 cm−1; H NMR (300
3-(p-Tolyl)benzofuro[3,2-c]quinoline (4o). A mixture of substrate
3b (0.150 g, 0.396 mmol), o-tolylboronic acid (0.059 g, 0.435 mmol),
Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous K2CO3 (0.109 g, 0.79
mmol) in anhydrous NMP (0.6 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above to give the
title product as a white solid; yield: 90 mg (74%); m.p. 200−202 °C;
MHz, CDCl3) δ: 7.46−7.70 (m, 5H), 7.79 (d, J = 8.3 Hz, 1H), 7.84−
8.04 (m, 6H), 8.05−8.20 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.71 (d, J
= 1.9 Hz, 1H), 9.53 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δ: 112.1, 116.8, 117.4, 119.0, 120.7, 122.6, 124.2, 127.3, 127.5, 128.4,
128.5, 130.0, 130.6, 130.9, 132.5, 136.8, 137.6, 138.4, 144.0, 144.7,
146.9, 156.0, 157.5, 196.2 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C28H18NO2 400.1332; found: 400.1331.
2-(3-Nitrophenyl)benzofuro[3,2-c]quinoline (4k). A mixture of
substrate 3a (0.150 g, 0.396 mmol), 3-nitrophenylboronic acid (0.072
g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous K2CO3
(0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL mmol−1)
1
IR (NaCl): ν 3150, 1554, 1450, 1379, 1190 cm−1; H NMR (300
MHz, CDCl3) δ: 2.45 (s, 3H), 7.34 (d, J = 7.9 Hz, 2H), 7.44−7.60
(m, 2H), 7.66−7.81 (m, 3H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 8.11 (dd,
J = 7.6, 0.9 Hz, 1H), 8.42−8.52 (m, 2H), 9.51 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 21.2, 112.1, 115.9, 116.2, 120.5, 121.1,
122.7, 124.0, 126.4, 127.1, 127.2, 127.3, 129.8, 137.3, 137.9, 142.0,
G
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The Journal of Organic Chemistry
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Article
144.7, 147.9, 156.0, 157.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H16NO 310.1232; found: 310.1244.
(m, 2H), 7.94 (dd, J = 8.9, 2.0 Hz, 1H), 8.11 (dd, J = 7.6, 0.8 Hz,
1H), 8.24 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 9.49 (s, 1H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ: 28.2, 80.9, 112.3, 117.0,
117.3, 120.8, 121.6, 122.0, 122.5, 124.3, 127.4, 127.6, 130.5, 133.4,
142.5, 145.1, 147.9, 156.1, 157.5, 166.1 ppm; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C22H20NO3: 346.1438; found: 346.1434.
tert-Butyl (E)-3-(Benzofuro[3,2-c]quinolin-3-yl)acrylate (5b). A
mixture of substrate 3b (0.050 g, 0.132 mmol), tert-butyl acrylate (21
μL, 0.145 mmol), Pd(OAc)2 (0.6 mg, 2 mol %), and anhydrous
K2CO3 (0.036 g, 0.264 mmol) in anhydrous NMP (0.2 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot MH/DA
procedure above to give the title product as a pale yellow solid; X-ray
quality crystals were obtained via vapor diffusion from a saturated
solution of toluene in hexane, the CCDC number is 1967537; yield:
36 mg (80%); m.p. 160−162 °C; IR (NaCl): ν 3393, 2976, 1703,
1560, 1452, 1366, 1285, 1149 cm−1; 1H NMR (300 MHz, CDCl3) δ:
1.58 (s, 9H), 6.59 (d, J = 16.0 Hz, 1H), 7.44−7.63 (m, 2H), 7.71−
7.92 (m, 3H), 8.11 (dd, J = 7.6, 0.8 Hz, 1H), 8.30−8.46 (m, 2H), 9.51
(s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 28.2, 80.8, 112.2,
117.1, 117.7, 120.8, 121.4, 122.0, 122.5, 124.3, 125.1, 127.6, 130.7,
135.6, 142.8, 145.2, 147.4, 156.2, 157.1, 166.0 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H20NO3: 346.1438; found:
346.1432.
3-(4-(Trifluoromethyl)phenyl)benzofuro[3,2-c]quinoline (4p). A
mixture of substrate 3b (0.150 g, 0.396 mmol), (4-(trifluoromethyl)-
phenyl)boronic acid (0.083 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2
mol %), and anhydrous K2CO3 (0.109 g, 0.79 mmol) in anhydrous
NMP (0.6 mL, 1.5 mL mmol−1) was reacted according to the general
one-pot SM/DA procedure above to give the title product as a yellow
solid; yield: 114 mg (79%); m.p. 205−208 °C; IR (NaCl): ν 3251,
1559, 1450, 1329, 1188, 1110 cm−1; 1H NMR (300 MHz, CDCl3) δ:
7.46−7.63 (m, 2H), 7.76−7.82 (m, 3H), 7.86−8.02 (m, 3H), 8.13
(dd, J = 7.6, 0.9 Hz, 1H), 8.49−8.57 (m, 2H), 9.55 (s, 1H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δ: 112.2, 116.7, 120.7, 121.6, 122.6,
1
3
124.21, 124.22 (q, J(C,F) = 270 Hz), 126.0 (q, J(C,F) = 4 Hz), 126.2,
2
127.5, 127.7, 128.2, 129.9 (q, J(C,F) = 32 Hz), 140.4, 143.7, 145.1,
147.6, 156.1, 157.3 ppm; 19F{1H} NMR (282 MHz, CDCl3) δ: −62
ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H13F3NO
364.0949; found: 364.0951. Note: 13C NMR shift at 116.7 ppm
represents two individual carbon signals as confirmed by 2D NMR
experiments.
4-(Benzofuro[3,2-c]quinolin-3-yl)benzonitrile (4q). A mixture of
substrate 3b (0.150 g, 0.396 mmol), 4-cyanophenylboronic acid
(0.065 g, 0.435 mmol), Pd(OAc)2 (4.4 mg, 5 mol %), and anhydrous
K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot SM/DA
procedure above to give the title product as a white solid; yield: 85 mg
(67%); m.p. >250 °C; IR (NaCl): ν 3348, 2223, 1553, 1447, 1344,
(E)-2-Styrylbenzofuro[3,2-c]quinoline (5c). A mixture of substrate
3a (0.114 g, 0.30 mmol), styrene (38 μL, 0.33 mmol), Pd(OAc)2 (3.4
mg, 5 mol %), and anhydrous K2CO3 (0.083 g, 0.60 mmol) in
anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was reacted according to
the general one-pot MH/DA procedure above to give the title
product as a white solid; yield: 70 mg (73%); m.p. 201−202 °C; IR
1
1184 cm−1; H NMR (300 MHz, CDCl3) δ: 7.45−7.64 (m, 2H),
7.73−7.80 (m, 6H), 8.13 (dd, J = 7.6, 0.8 Hz, 1H), 8.45−8.60 (m,
2H), 9.55 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 111.7,
112.3, 116.9, 117.0, 118.8, 120.8, 121.9, 122.6, 124.3, 126.0, 127.6,
128.1, 128.4, 132.9, 139.9, 144.7, 145.3, 147.5, 156.2, 157.2 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H13N2O: 321.1028;
found: 321.1033.
1
(NaCl) ν 3379, 1662, 1561, 1377, 1188 cm−1; H NMR (300 MHz,
CDCl3) δ: 7.22−7.66 (m, 9H), 7.76 (d, J = 8.1 Hz, 1H), 7.98 (dd, J =
8.9, 2.0 Hz, 1H), 8.07 (dd, J = 7.6, 0.8 Hz, 1H), 8.22 (d, J = 8.9 Hz,
1H), 8.39 (d, J = 1.8 Hz, 1H), 9.41 (s, 1H) ppm; 13C{1H} NMR (75
MHz, CDCl3) δ: 112.1, 116.7, 117.4, 118.6, 120.7, 122.7, 124.1,
126.8, 127.2, 127.3, 127.8, 128.1, 128.8, 130.1, 130.6, 136.1, 137.0,
143.9, 147.0, 156.0, 157.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H16NO 322.1226; found: 322.1223.
3-(4-Methoxyphenyl)benzofuro[3,2-c]quinoline (4r). A mixture of
substrate 3b (0.150 g, 0.396 mmol), 4-methoxyphenylboronic acid
(0.066 g, 0.435 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous
K2CO3 (0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot SM/DA
procedure above to give the title product as a white solid; yield: 88 mg
(70%); m.p. 157−158 °C; IR (NaCl): ν 3369, 2998, 1607, 1450,
1303, 1245, 1188 cm−1; 1H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3H),
6.99−7.10 (m, 2H), 7.41−7.57 (m, 2H), 7.68−7.77 (m, 3H), 7.91
(dd, J = 8.6, 1.7 Hz, 1H), 8.07 (dd, J = 7.5, 1.5 Hz, 1H), 8.37−8.45
(m, 2H), 9.47 (s, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ:
55.4, 112.1, 114.5, 115.7, 116.1, 120.5, 121.2, 122.8, 124.1, 126.3,
126.8, 127.1, 128.5, 132.7, 141.7, 144.8, 148.0, 156.0, 157.5, 159.8
ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H16NO2
326.1176; found: 326.1173.
(E)-2-(4-Methoxystyryl)benzofuro[3,2-c]quinoline (5d). A mixture
of substrate 3a (0.114 g, 0.30 mmol), 4-methoxystyrene (44 μL, 0.33
mmol), Pd(OAc)2 (3.4 mg, 5 mol %), and anhydrous K2CO3 (0.083
g, 0.60 mmol) in anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot MH/DA procedure above to
give the title product as a white solid; yield: 86 mg (82%); m.p. 190−
192 °C; IR (NaCl) ν 3388, 1656, 1602, 1562, 1346, 1250, 1110 cm−1;
1H NMR (300 MHz, CDCl3) δ: 3.86 (s, 3H), 6.84−7.04 (m, 2H),
7.12−7.38 (m, 2H), 7.40−7.65 (m, 4H), 7.76 (d, J = 8.1 Hz, 1H),
7.97 (dd, J = 8.9, 1.8 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 8.21 (d, J =
8.9 Hz, 1H), 8.38 (d, J = 1.7 Hz, 1H), 9.41 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 55.4, 112.1, 114.3, 116.7, 117.5, 118.1,
120.7, 122.8, 124.1, 125.7, 127.2, 127.3, 128.0, 129.8, 130.1, 130.2,
136.5, 143.7, 146.9, 156.0, 157.4, 159.7 ppm; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C24H18NO2 352.1332; found: 352.1328.
(E)-2-(4-Fluorostyryl)benzofuro[3,2-c]quinoline (5e). A mixture of
substrate 3a (0.114 g, 0.30 mmol), 4-fluorostyrene (39 μL, 0.33
mmol), Pd(OAc)2 (3.4 mg, 5 mol %), and anhydrous K2CO3 (0.083
g, 0.60 mmol) in anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot MH/DA procedure above to
give the title product as a yellow solid; yield: 82 mg (80%); m.p. 189−
191 °C; IR (NaCl) ν 3404, 1676, 1598, 1559, 1346, 1234, 1096 cm−1;
1H NMR (300 MHz, CDCl3) δ: 7.00−7.15 (m, 2H), 7.17−7.34 (m,
2H), 7.41−7.63 (m, 4H), 7.75 (d, J = 8.1 Hz, 1H), 7.95 (dd, J = 8.9,
2.0 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.37
(d, J = 1.8 Hz, 1H), 9.41 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
General Procedure for Palladium-Catalyzed One-Pot Miz-
oroki−Heck and Intramolecular Direct Arylation Reactions. A
mixture of the 4-(2-bromophenoxy)quinoline substrate (1 equiv),
Heck coupling partner (1.1 equiv), Pd(OAc)2 (2 mol % for tert-butyl
acrylate or 5 mol % for styrene derivatives), and anhydrous K2CO3 (2
equiv) in anhydrous NMP (1.5 mL mmol−1) was stirred at 135 °C in
a sealed reaction tube in an aluminum multireaction heating mantle
1
until the reaction was completed as evidenced by H NMR analysis
(18−24 h). The cooled reaction mixture was diluted with DCM,
filtered through a short plug of Celite, and concentrated in vacuo. The
crude mixture was purified by column chromatography over silica gel
using DCM/EtOAc (99:1−95:5) as an eluent.
tert-Butyl (E)-3-(Benzofuro[3,2-c]quinolin-2-yl)acrylate (5a). A
mixture of substrate 3a (0.050 g, 0.132 mmol), tert-butyl acrylate (21
μL, 0.145 mmol), Pd(OAc)2 (0.6 mg, 2 mol %), and anhydrous
K2CO3 (0.036 g, 0.264 mmol) in anhydrous NMP (0.2 mL, 1.5 mL
mmol−1) was reacted according to the general one-pot MH/DA
procedure above to give the title product as a white solid; yield: 27 mg
(60%); m.p. 169−170 °C; IR (NaCl): ν 3393, 2976, 1701, 1560,
2
CDCl3) δ: 112.1, 115.8 (d, J(C,F) = 22 Hz), 116.7, 117.4, 118.6,
6
120.7, 122.7, 124.1, 127.1, 127.3, 127.6 (d, J(C,F) = 2 Hz), 128.3 (d,
4
3J(C,F) = 8 Hz), 129.4, 130.2, 133.2 (d, J(C,F) = 3 Hz), 135.9, 144.0,
1
147.0, 156.0, 157.4, 162.6 (d, J(C,F) = 248 Hz) ppm; 19F{1H} NMR
1460, 1366, 1238, 1151 cm−1; H NMR (300 MHz, CDCl3) δ: 1.58
(282 MHz, CDCl3) δ: −113 ppm; HRMS (ESI-TOF) m/z: [M + H]+
1
(s, 9H), 6.60 (d, J = 16.0 Hz, 1H), 7.44−7.65 (m, 2H), 7.73−7.89
calcd for C23H15FNO 340.1132; found: 340.1135.
H
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(E)-3-Styrylbenzofuro[3,2-c]quinoline (5f). A mixture of substrate
3b (0.114 g, 0.30 mmol), styrene (38 μL, 0.33 mmol), Pd(OAc)2 (3.4
mg, 5 mol %), and anhydrous K2CO3 (0.083 g, 0.60 mmol) in
anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was reacted according to
the general one-pot MH/DA procedure above to give the title
product as a yellow solid; yield: 72 mg (75%); m.p. 179−182 °C; IR
was reacted according to the general one-pot MH/DA procedure
above to give the title product as a white solid; yield: 50 mg (73%);
m.p. 157−158 °C; IR (NaCl) ν 3434, 1703, 1638, 1594, 1566, 1367,
1203, 1151 cm−1; 1H NMR (300 MHz, CDCl3) δ: 1.58 (s, 9H), 6.47
(d, J = 15.9 Hz, 1H), 7.50−7.89 (m, 5H), 8.09−8.30 (m, 2H), 8.36
(dd, J = 8.1, 1.1 Hz, 1H), 9.45 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 28.3, 80.7, 112.5, 115.9, 117.1, 120.2, 120.4, 120.8, 123.5,
127.22, 127.24, 129.6, 130.0, 131.2, 143.0, 144.3, 147.7, 156.7, 158.2,
166.2 ppm; HRMS (ESI-TOF) m/z: [M + H]+ C22H20NO3:
346.1438; found: 346.1430.
1
(NaCl) ν 3583, 1656, 1632, 1561, 1348, 1190 cm−1; H NMR (300
MHz, CDCl3) δ: 7.20−7.65 (m, 9H), 7.74 (d, J = 7.9 Hz, 1H), 7.91
(dd, J = 8.6, 1.5 Hz, 1H), 8.07 (dd, J = 7.5, 0.9 Hz, 1H), 8.27 (d, J =
1.3 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 9.46 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 112.1, 116.3, 120.6, 121.1, 122.7, 124.1,
124.9, 126.8, 127.2, 128.0, 128.1, 128.8, 130.7, 137.0, 138.5, 144.8,
147.9, 156.1, 157.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H16NO 322.1226; found: 322.1227. Note: 13C NMR shifts at
116.3 and 128.1 ppm represent two individual carbon signals as
confirmed by 2D NMR experiments.
(E)-8-Styrylbenzofuro[3,2-c]quinoline (6c). A mixture of substrate
3e (0.076 g, 0.20 mmol), styrene (25 μL, 0.22 mmol), Pd(OAc)2 (2.5
mg, 5 mol %), and anhydrous K2CO3 (0.055 g, 0.40 mmol) in
anhydrous NMP (0.3 mL, 1.5 mL mmol−1) was reacted according to
the general one-pot MH/DA procedure above to give the title
product as a yellow solid; yield: 25 mg (40%); m.p. 200−203 °C; IR
1
(NaCl) ν 3583, 1650, 1598, 1567, 1324, 1195 cm−1; H NMR (300
(E)-3-(4-Methoxystyryl)benzofuro[3,2-c]quinoline (5g). A mixture
of substrate 3b (0.114 g, 0.30 mmol), 4-methoxystyrene (44 μL, 0.33
mmol), Pd(OAc)2 (3.4 mg, 5 mol %), and anhydrous K2CO3 (0.083
g, 0.60 mmol) in anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot MH/DA procedure above to
give the title product as a yellow solid; yield: 84 mg (80%); m.p. 168−
170 °C; IR (NaCl) ν 3379, 1687, 1603, 1560, 1347, 1176, 1033 cm−1;
1H NMR (300 MHz, CDCl3) δ: 3.86 (s, 3H), 6.89−7.00 (m, 2H),
7.13−7.39 (m, 2H), 7.42−7.65 (m, 4H), 7.75 (d, J = 7.8 Hz, 1H),
7.92 (dd, J = 8.6, 1.5 Hz, 1H), 8.09 (dd, J = 7.2, 1.3 Hz, 1H), 8.27 (d,
J = 1.2 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 9.47 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δ: 55.4, 112.1, 114.3, 116.0, 116.2, 120.5,
121.0, 122.8, 124.1, 124.8, 126.0, 127.1, 127.5, 128.1, 129.8, 130.3,
138.9, 144.7, 148.0, 156.0, 157.4, 159.7 ppm; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C24H18NO2 352.1332; found: 352.1333.
(E)-3-(4-Fluorostyryl)benzofuro[3,2-c]quinoline (5h). A mixture of
substrate 3b (0.114 g, 0.30 mmol), 4-fluorostyrene (39 μL, 0.33
mmol), Pd(OAc)2 (3.4 mg, 5 mol %), and anhydrous K2CO3 (0.083
g, 0.60 mmol) in anhydrous NMP (0.5 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot MH/DA procedure above to
give the title product as a yellow solid; yield: 63 mg (62%); m.p. 209−
211 °C; IR (NaCl) ν 3049, 1682, 1637, 1508, 1347, 1228, 1012 cm−1;
1H NMR (300 MHz, CDCl3) δ: 7.02−7.16 (m, 2H), 7.20−7.38 (m,
2H), 7.42−7.64 (m, 4H), 7.76 (dd, J = 7.6, 0.7 Hz, 1H), 7.91 (dd, J =
8.6, 1.6 Hz, 1H), 8.04−8.15 (m, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.39
(d, J = 8.6 Hz, 1H), 9.48 (s, 1H), ppm; 13C{1H} NMR (75 MHz,
MHz, CDCl3) δ: 7.11−7.47 (m, 5H), 7.55−7.61 (m, 2H), 7.63−7.87
(m, 4H), 8.11−8.32 (m, 2H), 8.39 (dd, J = 8.1, 1.3 Hz, 1H), 9.50 (s,
1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 112.2, 116.2, 117.2,
118.2, 120.8, 123.3, 126.0, 126.5, 127.1, 127.8, 128.1, 128.8, 128.9,
129.4, 129.9, 133.9, 137.2, 144.4, 147.5, 155.6, 158.0 ppm; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C23H16NO 322.1226; found:
322.1223.
General Procedure for the Synthesis of Three-Component
SM/DA and MH/DA Products. The same procedures and
purification methods outlined for the SM/DA and MH/DA reactions
were employed here using bromo-4-(2,4-dibromphenoxy)quinoline
(1 equiv) as the substrate and double the equivalent of coupling
partner (2.2 equiv).
2,8-Diphenylbenzofuro[3,2-c]quinoline (7a). A mixture of sub-
strate 3f (0.200 g, 0.437 mmol), phenylboronic acid (0.117 g, 0.96
mmol), Pd(OAc)2 (2.0 mg, 2 mol %), and anhydrous K2CO3 (0.121
g, 0.873 mmol) in anhydrous NMP (0.7 mL, 1.5 mL mmol−1) was
reacted according to the general one-pot SM/DA procedure above to
give the title product as a pale yellow solid; yield: 129 mg (80%); m.p.
206−207 °C; IR (NaCl): ν 3054, 2920, 1682, 1560, 1460, 1358, 1200
1
cm−1; H NMR (300 MHz, CDCl3) δ: 7.37−7.60 (m, 6H), 7.68−
7.88 (m, 6H), 8.07 (dd, J = 8.8, 2.1 Hz, 1H), 8.28−8.40 (m, 2H), 8.64
(d, J = 1.7 Hz, 1H), 9.54 (s, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δ: 112.2, 116.6, 117.4, 118.4, 119.1, 123.3, 126.8, 127.4,
127.50, 127.54, 128.0, 128.9, 129.0, 130.3, 137.9, 139.8, 140.1, 140.9,
144.2, 146.8, 155.5, 158.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C27H18NO 372.1388; found: 372.1384. Note: 13C NMR
shift at 128.9 ppm represents two individual carbon signals as
confirmed by 2D NMR experiments.
2
CDCl3) δ: 112.1, 115.8 (d, J(C,F) = 22 Hz), 116.31, 116.34, 120.6,
121.1, 122.7, 124.1, 124.8, 127.3, 127.86, 127.89, 128.3 (d, 3J(C,F) = 8
Hz), 129.4, 133.2 (d, 4J(C,F) = 3 Hz), 138.3, 144.8, 147.9, 156.0, 157.4,
1
162.6 (d, J(C,F) = 248 Hz) ppm; 19F{1H} NMR (282 MHz, CDCl3)
δ: −113 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H15FNO 340.1132; found: 340.1135.
Di-tert-butyl 3,3′-(Benzofuro[3,2-c]quinoline-3,8-diyl)(2E,2′E)-di-
acrylate (7b). A mixture of substrate 3g (0.050 g, 0.11 mmol), tert-
butyl acrylate (35 μL, 0.242 mmol), Pd(OAc)2 (0.5 mg, 2 mol %),
and anhydrous K2CO3 (0.030 g, 0.22 mmol) in anhydrous NMP (0.3
mL, 1.5 mL mmol−1) was reacted according to the general one-pot
MH/DA procedure above to give the title product as a white solid;
yield: 23 mg (43%); m.p. 217−219 °C; IR (NaCl) ν 3402, 1703,
1638, 1559, 1512, 1368, 1201, 1148 cm−1; 1H NMR (300 MHz,
CDCl3) δ: 1.50−1.61 (m, 18H), 6.40−6.67 (m, 2H), 7.66−7.94 (m,
5H), 8.23 (d, J = 0.8 Hz, 1H), 8.29−8.44 (m, 2H), 9.49 (s, 1H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δ: 28.22, 28.24, 80.7, 80.9, 112.6,
General Procedure for the Synthesis of Phenoxy-Substi-
tuted SM/DA and MH/DA Products. The same procedures and
purification methods outlined for the SM/DA and MH/DA reactions
were employed here using 4-(2,4-dibromphenoxy)quinoline 3e (1
equiv) as the substrate.
8-Phenylbenzofuro[3,2-c]quinoline (6a). A mixture of substrate
3e (0.200 g, 0.528 mmol), phenylboronic acid (0.071 g, 0.58 mmol),
Pd(OAc)2 (2.4 mg, 2 mol %), and anhydrous K2CO3 (0.146 g, 1.06
mmol) in anhydrous NMP (0.8 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot SM/DA procedure above to give the
title product as a yellow solid; yield: 103 mg (65%); m.p. 153−155
°C; IR (NaCl): ν 2922, 1567, 1460, 1325, 1202 cm−1; 1H NMR (300
MHz, CDCl3) δ: 7.36−7.45 (m, 1H), 7.46−7.56 (m, 2H), 7.67−7.86
(m, 6H), 8.24−8.35 (m, 2H), 8.45 (dd, J = 8.1, 1.6 Hz, 1H), 9.55 (s,
1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 112.2, 116.4, 117.2,
119.1, 120.8, 123.3, 126.7, 127.1, 127.4, 127.5, 128.9, 129.4, 129.9,
137.9, 140.9, 144.4, 147.5, 155.5, 158.0 ppm; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C21H14NO 296.1070; found: 296.1072.
tert-Butyl (E)-3-(Benzofuro[3,2-c]quinolin-8-yl)acrylate (6b). A
mixture of substrate 3e (0.076 g, 0.20 mmol), tert-butyl acrylate (32
μL, 0.22 mmol), Pd(OAc)2 (0.9 mg, 2 mol %), and anhydrous K2CO3
(0.055 g, 0.40 mmol) in anhydrous NMP (0.3 mL, 1.5 mL mmol−1)
116.6, 117.6, 120.3, 120.5, 121.4, 122.3, 123.3, 125.3, 127.5, 130.7,
131.4, 136.0, 142.7, 142.8, 145.0, 147.7, 156.9, 157.8, 166.0, 166.1
ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H30NO5:
472.2118; found: 472.2117.
3,8-Di((E)-styryl)benzofuro[3,2-c]quinoline (7c). A mixture of
substrate 3g (0.115 g, 0.25 mmol), styrene (63 μL, 0.55 mmol),
Pd(OAc)2 (2.8 mg, 5 mol %), and anhydrous K2CO3 (0.069 g, 0.50
mmol) in anhydrous NMP (0.4 mL, 1.5 mL mmol−1) was reacted
according to the general one-pot MH/DA procedure above to give
the title product as a white solid; yield: 76 mg (36%); m.p. >250 °C;
1
IR (NaCl) ν 3387, 1691, 1594, 1560, 1326, 1044 cm−1; H NMR
(600 MHz, (CD3)2SO) δ: 7.20−7.54 (m, 9H), 7.59 (app. s, 2H),
7.63−7.75 (m, 4H), 7.87 (dd, J = 8.6, 1.6 Hz, 1H), 7.94 (d, J = 8.5
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Hz, 1H), 8.17 (dd, J = 8.7, 1.4 Hz, 1H), 8.35 (d, J = 1.3 Hz, 1H), 8.41
(d, J = 8.5 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 9.69 (s, 1H) ppm;
13C{1H} NMR (150 MHz, (CD3)2SO) δ: 112.8, 115.9, 116.4, 119.1,
121.4, 123.2, 127.0, 127.2, 127.3, 128.29, 128.33, 128.6, 129.0, 129.3,
131.2, 134.3, 137.3, 137.5, 139.0, 146.0, 148.1, 155.5, 157.4 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H22NO 424.1696;
found: 424.1690. Note: This compound was highly insoluble, spectra
were acquired on <3 mg of this compound after heating in (CD3)2SO,
and it was difficult to directly assign. As with other compounds, some
13C shifts from this spectrum represent more than one signal as
saturated solution of toluene/methanol in hexane, the CCDC number
is 1970630; decomposition >150 °C; IR (NaCl) ν 3436, 1615, 1589,
1
1573, 1303, 1217, 1075, 695 cm−1; H NMR (300 MHz, CDCl3) δ:
1.53 (s, 6H), 6.47 (d, J = 6.2 Hz, 2H), 7.11−7.34 (m, 4H), 7.37−7.54
(m, 2H), 7.59−7.84 (m, 4H), 8.08 (ddd, J = 8.6, 7.0, 1.4 Hz, 2H),
8.41 (dd, J = 8.1, 0.9 Hz, 2H), 9.46 (d, J = 6.2 Hz, 2H), 10.20 (d, J =
8.6 Hz, 2H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ: 22.6, 103.9,
116.2, 121.3, 122.0, 123.4, 127.4, 128.1, 129.0, 129.4, 132.1, 134.5,
147.9, 150.2, 156.1, 162.6, 178.3 ppm; HRMS (ESI-TOF) m/z: [M −
OAc]+ calcd for C32H23Br2N2O4Pd 762.9054; found: 762.9081.
7-Bromo-4-(2-bromophenoxy)quinoline Palladium Diacetate
Dimer (8b). To an NMR tube were added 3b (60.8 mg, 0.160
mmol, 1.0 equiv), Pd(OAc)2 (18.0 mg, 0.080 mmol, 0.5 equiv), and
CDCl3 (0.6 mL). Decomposition >190 °C; IR (NaCl) ν 3419, 1623,
confirmed by 2D NMR experiments.
Isolation of Suzuki−Miyaura Only Products. To further probe
the hypothesis that the Suzuki−Miyaura reaction was occurring at the
C-6 position before direct arylation at the C-3 position, substrate 3i
was synthesized. This substrate could only undergo the Suzuki−
Miyaura reaction and proceeded as anticipated (Supporting
Information Scheme S1).
1
1590, 1511, 1306, 1219, 1063, 733, 693 cm−1; H NMR (600 MHz,
CDCl3) δ: 1.59 (s, 6H), 6.46 (d, J = 6.2 Hz, 2H), 7.16−7.37 (m, 4H),
7.41−7.57 (m, 2H), 7.66−7.93 (m, 4H), 8.29 (d, J = 8.8 Hz, 2H),
9.43 (d, J = 6.2 Hz, 2H), 10.36 (d, J = 1.7 Hz, 2H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ: 22.7, 104.2, 116.1, 120.1, 123.3, 123.5,
127.0, 128.4, 129.6, 131.2, 134.6, 148.4, 149.9, 157.4, 162.8, 178.4
4-Phenoxy-6-phenylquinoline (4s). A mixture of substrate 3i
(0.200 g, 0.666 mmol, 1 equiv), phenylboronic acid (0.081 g, 0.666
mmol, 1 equiv), Pd(OAc)2 (3.0 mg, 2 mol %), and anhydrous K2CO3
(0.184 g, 1.333 mmol, 2 equiv) in anhydrous NMP (1.0 mL, 1.5 mL
mmol−1) was stirred at 135 °C in a sealed reaction tube in an
aluminum multireaction heating mantle until the reaction was
completed as evidenced by 1H NMR analysis (4 h). The cooled
reaction mixture was diluted with DCM, filtered through a short plug
of Celite, and concentrated in vacuo. The crude mixture was purified
by column chromatography over silica gel using Hex/EtOAc (7:3−
6:4) as an eluent to give the title product as a pale yellow solid; yield:
168 mg (84%); m.p. 78−80 °C; IR (NaCl): ν 3058, 1562, 1487,
1460, 1360, 1203 cm−1; 1H NMR (300 MHz, CDCl3) δ: 6.58 (d, J =
5.1 Hz, 1H), 7.16−7.57 (m, 8H), 7.72−7.74 (m, 2H), 8.03 (dd, J =
8.8, 2.1 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H),
8.67 (d, J = 4.9 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ:
104.6, 119.6, 121.2, 121.7, 125.7, 127.5, 127.7, 129.0, 129.6, 129.8,
130.3, 139.0, 140.5, 149.1, 151.1, 154.4, 162.1 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H16NO 298.1226; found:
298.1228.
ppm; HRMS (ESI-TOF) m/z: [M
−
OAc]+ calcd for
C32H21Br4N2O4Pd 918.7264; found: 918.7284. Note: 13C NMR
shift at 131.2 ppm represents two individual carbon signals as
confirmed by 2D NMR experiments.
4-Phenoxyquinoline Palladium Diacetate Dimer (8c). To 25 mL
of RBF were added 3h (55.0 mg, 0.249 mmol, 1.0 equiv), Pd(OAc)2
(27.9 mg, 0.124 mmol, 0.5 equiv), and CDCl3 (2 mL); X-ray quality
crystals were obtained via vapor diffusion from a saturated solution of
toluene/methanol in hexane, the CCDC number is 1970507;
decomposition >150 °C; IR (NaCl) ν 3413, 1621, 1595, 1305,
1512, 1203, 1063 cm−1; 1H NMR (300 MHz, CDCl3) δ: 1.53 (s, 6H),
6.50 (d, J = 6.2 Hz, 2H), 7.03−7.21 (m, 4H), 7.23−7.51 (m, 6H),
7.61 (ddd, J = 8.2, 7.0, 1.0 Hz, 2H), 7.99 (ddd, J = 8.6, 7.0, 1.4 Hz,
2H), 8.28 (dd, J = 8.4, 1.0 Hz, 2H), 9.34 (d, J = 6.2 Hz, 2H), 10.08
(d, J = 8.6 Hz, 2H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δ: 22.7,
104.3, 121.4, 121.8, 122.0, 126.7, 127.3, 129.1, 130.7, 132.0, 148.0,
153.4, 156.1, 163.9, 178.3 ppm; HRMS (ESI-TOF) m/z: [M −
OAc]+ calcd for C32H25N2O4Pd 607.0844; found: 607.0849.
The tandem reaction was carried out on 3a at a lower temperature
to see if the Suzuki−Miyaura only product could be isolated and
prove that it was happening prior to the direct arylation reaction. At
this temperature, the major product was the uncyclized Suzuki−
Miyaura product 4t, although some of the tandem product 4a and
starting material 3a were also isolated (Supporting Information
Scheme S2).
Experiments To Prove Viability of Palladium−Quinoline
Complexes. 1. A 0.062 M stock solution of 8c in CDCl3 was
prepared, and 0.1 mL (4.1 mg, 2 mol %) was transferred to a reaction
tube and concentrated in vacuo to give a yellow residue. To the tube
containing this residue were added substrate 3a (0.118 g, 0.310 mmol,
1 equiv), phenylboronic acid (0.042 g, 0.341 mmol, 1.1 equiv),
anhydrous K2CO3 (0.086 g, 0.62 mmol), and NMP (0.5 mL, 1.5 mL
mmol−1). The resulting mixture was stirred at 135 °C in the sealed
reaction tube in an aluminum multireaction heating mantle until the
reaction was complete as evidenced by 1H NMR analysis (20 h). The
cooled reaction mixture was diluted with DCM, filtered through a
short plug of Celite, and concentrated in vacuo. A yield of 81% 4a was
4-(2-Bromophenoxy)-6-phenylquinoline (4t). A mixture of
substrate 3a (0.150 g, 0.396 mmol), phenylboronic acid (0.048 g,
0.396 mmol), Pd(OAc)2 (1.8 mg, 2 mol %), and anhydrous K2CO3
(0.109 g, 0.79 mmol) in anhydrous NMP (0.6 mL, 1.5 mL mmol−1)
was stirred at 100 °C in a sealed reaction tube in an aluminum
multireaction heating mantle for 24 h. The cooled reaction mixture
was diluted with DCM, filtered through a short plug of Celite, and
concentrated in vacuo. The crude mixture was purified by column
chromatography over silica gel using Hex/EtOAc (8:2−7:3) as an
eluent to give the title product as a pale yellow solid; yield: 73 mg
(49%); m.p. 85−87 °C; IR (NaCl): ν 3059, 1564, 1460, 1361, 1222,
667 cm−1; 1H NMR (300 MHz, CDCl3) δ: 6.43 (d, J = 5.2 Hz, 1H),
7.16−7.32 (m, 2H), 7.34−7.57 (m, 4H), 7.70−7.84 (m, 3H), 8.05
(dd, J = 8.8, 2.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.62 (d, J = 2.0 Hz,
1H), 8.69 (d, J = 5.3 Hz, 1H) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δ: 103.9, 116.4, 119.6, 121.3, 123.3, 127.6, 127.9, 129.0, 129.3, 130.2,
134.4, 139.4, 140.3, 148.2, 150.5, 151.0, 161.5 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H15BrNO 376.0332; found:
376.0331. Note: 13C NMR shifts at 127.6 and 129.0 ppm each
represent two individual carbon signals as confirmed by 2D NMR
experiments.
1
determined by H NMR analysis of the crude reaction mixture using
1,3,5-trimethoxybenzene as an internal standard (Scheme 4a).
2. A 0.062 M stock solution of 8c in CDCl3 was prepared, and 0.1
mL (4.1 mg, 2 mol %) was transferred to a reaction tube and
concentrated in vacuo to give a yellow residue. To the tube containing
this residue were added substrate 1 (0.093 g, 0.310 mmol, 1 equiv),
anhydrous K2CO3 (0.086 g, 0.62 mmol), and NMP (0.5 mL, 1.5 mL
mmol−1). The resulting mixture was stirred at 135 °C in the sealed
reaction tube in an aluminum multireaction heating mantle until the
reaction was complete as evidenced by 1H NMR analysis (20 h). The
cooled reaction mixture was diluted with DCM, filtered through a
short plug of Celite, and concentrated in vacuo. A 99% yield of 2 was
1
determined by H NMR analysis of the crude reaction mixture using
1,3,5-trimethoxybenzene as an internal standard (Supporting
Information Scheme S3).
3. A 0.10 M stock solution of 8a in CHCl3 was prepared, and 0.2
mL (16.5 mg, 10 mol %) was transferred to a reaction tube and
concentrated in vacuo to give a yellow residue. To the tube containing
this residue were added substrate 3a (0.076 g, 0.20 mmol, 1 equiv),
phenylboronic acid (0.027 g, 0.22 mmol, 1.1 equiv), anhydrous
The Synthesis of Palladium−Quinoline Complexes. 4-(2-
Bromophenoxy)quinoline Palladium Diacetate Dimer (8a). To an
NMR tube were added 1 (61.5 mg, 0.204 mmol, 1.0 equiv),
Pd(OAc)2 (22.9 mg, 0.102 mmol, 0.5 equiv), and CDCl3 (0.6 mL);
X-ray quality crystals were obtained via vapor diffusion from a
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K2CO3 (0.055 g, 0.40 mmol), and NMP (0.3 mL, 1.5 mL mmol−1).
The resulting mixture was stirred at 135 °C in the sealed reaction tube
in an aluminum multi-reaction heating mantle until the reaction was
complete as evidenced by 1H NMR analysis (18 h). The cooled
reaction mixture was diluted with DCM, filtered through a short plug
of Celite, and concentrated in vacuo. Upon analysis of the crude
reaction mixture, no starting material remained, and the peaks for
both products 4a and 2 were present. The signals for 4a and 2 were
too close to obtain accurate NMR yields and were nonseparable by
column chromatography (Scheme 4b).
the financial support of SFI through a research infrastructure
award for process flow spectroscopy (Prospect) under the
grant number 15/RI/3221.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03321.
■
sı
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AUTHOR INFORMATION
Corresponding Author
Gerard P. McGlacken − School of Chemistry, Analytical and
Biological Chemistry Research Facility (ABCRF) and Synthesis
and Solid State Pharmaceutical Centre (SSPC), University
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0002-7821-0804; Email: g.mcglacken@ucc.ie
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Authors
Rachel M. Shanahan − School of Chemistry, Analytical and
Biological Chemistry Research Facility (ABCRF), University
College Cork, Cork T12 YN60, Ireland
Aobha Hickey − School of Chemistry, Analytical and Biological
Chemistry Research Facility (ABCRF), University College Cork,
Cork T12 YN60, Ireland
Lorraine M. Bateman − School of Chemistry, Analytical and
Biological Chemistry Research Facility (ABCRF), Synthesis and
Solid State Pharmaceutical Centre (SSPC), and School of
Pharmacy, University College Cork, Cork T12 YN60, Ireland
Mark E. Light − Department of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03321
Author Contributions
⊥R.M.S. and A.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
2011, 13, 4236−4239. (e) Leclerc, J.-P.; Andre, M.; Fagnou, K. Heck,
The authors would like to thank Dr. Trevor Carey, Prof John
Sodeau, Dr. Peter Byrne, and Dr. Leticia Pardo for useful
discussion. The authors acknowledge the Irish Research
Council (IRC) and Science Foundation Ireland (SFI) (grant
number SFI/12/IP/1315) and the Synthesis and Solid State
Pharmaceutical Centre (SSPC) (SFI/12/RC/2275 and SFI/
12/RC/2275_P2). The authors thank the European Cooper-
ation in Science and Technology COST initiative for funding
CA15106, C-H Activation in Organic Synthesis (CHAOS).
This publication has emanated from research conducted with
Direct Arylation, and Hydrogenation: Two or Three Sequential
Reactions from a Single Catalyst. J. Org. Chem. 2006, 71, 1711−1714.
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The Journal of Organic Chemistry
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