Synthesis of Benzofuroquinolines via Phosphine-Free Direct Arylation of 4-Phenoxyquinolines in Air

Article abstract of DOI:10.1002/ejoc.201800923

A palladium-catalysed, phosphine-free, direct arylation of 4-phenoxyquinolines, in air is described. Using an intramolecular approach, the ring-closed products are formed in yields of up to 95 %. This approach allows access to a range of benzofuroquinolines. An array of functional groups on both the quinoline and phenoxy rings are tolerated.

Full text of DOI:10.1002/ejoc.201800923

A Journal of
Accepted Article
Title: Synthesis of benzofuroquinolines via phosphine-free C-H
activation of 4-phenoxyquinolines in air
Authors: Gerard P. McGlacken, Rachel Shanahan, Aobha Hickey, F.
Jerry Reen, and Fergal O'Gara
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800923
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800923
Supported by

10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
Synthesis of benzofuroquinolines via phosphine-free direct
arylation of 4-phenoxyquinolines in air.
Rachel M. Shanahan,[a] Aobha Hickey,[a] F. Jerry Reen,[b] Fergal O’Gara[c,d] and Gerard P.
McGlacken*[a]
Abstract: A palladium-catalysed, phosphine-free, direct arylation of
require specialised catalyst/ligand systems and are therefore less
4-phenoxyquinolines, in air is described. Using an intramolecular
approach, the ring-closed products are formed in yields of up to 95%.
This approach allows access to a range of benzofuroquinolines. An
array of functional groups on both the quinoline and phenoxy rings are
tolerated.
prevalent in the literature.[21] One of the earliest relevant examples
of an intramolecular direct arylation of a heteroarene was reported
in 1984 by Ames and Opalko.[22] As a recent example, Ha et al.
reported a palladium-catalysed synthesis of benzofuropyridines in
moderate to excellent yields.[23]
Herein we report a palladium-catalysed direct arylation of 4-
phenoxyquinolines as a route to benzofuro[3,2-c]quinolines
(Figure 1). Access to these products will aid exploration of their
untapped biological potential, given that similar quinoline-based
Introduction
compounds
exhibit
anticancer,[24]
antimalarial[25]
and
antibacterial[26] effects.
The quinoline nucleus occurs in many natural and synthetic
pharmacologically active compounds,[1] and is ranked 22nd in the
top 100 most frequently used ring systems present in FDA
approved drugs.[2] Thus, the quinoline motif is considered a
privileged biological scaffold, utilised by synthetic chemists to
build molecular complexity, and ultimately improve biological
activity. As a versatile heterocycle, it displays reactivity similar to
that of other aromatic (pyridine/benzene) analogues, and thus can
undergo a wide range of synthetic transformations.[3-4]
mol%
2
2
O
N
Pd(OAc)2
Cs2CO3
O
equiv.
5
8
4
Br
NMP
135 °C, Air
3
2
6
7
N
examples
24
to 95%
1
Up
No added
yield
ligand
In air
Figure 1. Intramolecular direct arylation of 4-phenoxyquinolines.
One of the most important transformations in organic synthesis
remains the linking of two (hetero)aryl groups via a new carbon-
carbon bond.[5] Traditionally, the most reliable class of C-C bond
forming reactions involves the palladium-catalysed coupling of an
aryl or vinyl halide with an organometallic reagent.[6-9] Examples
include the Suzuki-Miyaura coupling,[10] Stille coupling,[11] and
Negishi coupling.[12] An alternative is the use of direct arylation
protocols, which are less reliant on the installation of a reactive
functionality prior to cross-coupling.[13-15]
Previous syntheses of some of these substrates via direct
arylation have relied upon positioning the activated carbon-halide
on the C-3 position of the quinoline coupling partner[27-28] which
limits the accessibility and versatility of products formed. The first
example of non-directed direct arylation/C-H activation of the C-3
position of pyridines and quinolines was reported by Yu and co-
workers (Figure 2(i)), using phenanthroline ligands under inert
reaction conditions.[29] This method also relies upon the use of a
large excess of the quinoline or pyridine substrate, which is only
applicable to an intermolecular system. Herein we describe a
system that requires no added ligand for arylation of the C-3
position of the quinoline ring, via intramolecular direct arylation, in
air (Figure 2 (ii)).
Direct arylation of simple arenes has been increasingly utilised in
organic synthesis to access complex polycyclic ring systems.[16-20]
By comparison, similar reactions involving heterocycles tend to
[a]
Analytical and Biological Research Facility (ABCRF) &
School of Chemistry,
Yu et al., J. Am. Chem. Soc, 2011, 133, 19090:
University College Cork, Cork, Ireland
E-mail: g.mcglacken@ucc.ie
http://research.ucc.ie/profiles/D004/gmcglacken
School of Microbiology
University College Cork, Cork, Ireland
BIOMERIT Research Centre,
School of Microbiology,
I
H
+
PdII
(i)
Ligand
N2
[b]
[c]
N
O
N
(excess)
work:
This
University College Cork, Cork, Ireland
School of Biomedical Sciences,
Curtin Health Innovation Research Institute,
Curtin University, Perth, WA 6102, Australia
O
[d]
Br
PdII
(ii)
No added
ligand
N
N
Air
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Figure 2. Palladium-catalysed direct arylation at the C-3 position of quinolines.
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10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
the reaction could tolerate a variety of functional groups on both
the phenoxy and quinoline coupling partners. Substrates bearing
weakly electron-withdrawing substituents (2b-f) on the phenoxy
ring were well tolerated. Additionally, the chlorides in 2e and 2f
were retained as a synthetic handle for further cross-coupling.
The more strongly electron-withdrawing substituents on 2g and
2h led to cyclisation in excellent yields of 88% and 90%,
respectively. Moderate yields were observed in the case of the
nitro (2i) and ester (2j) analogues.
Initially, 4-(2-bromophenoxy)quinoline 1a was chosen as a model
substrate, which was readily accessible from reaction of 4-
chloroquinoline and 2-bromophenol. Our initial coupling
conditions allowed formation of the fused product 2a in 57%
isolated yield in air (Table 1 entry 1). Next, a variety of reaction
parameters was accessed (Table 1). A solvent screen indicated
that high-boiling point amide solvents were necessary for good
conversion (entries 1-3). Other organic solvents gave little or no
conversion to product (entries 4-8). Changing the base from
Na2CO3 to K2CO3 or Cs2CO3 allowed the reaction to reach 100%
conversion (entry 9 and 10), while use of a stronger butoxide base
resulted in partial decomposition of the starting material (entry
11). A further reduction in catalyst loading to 2 mol% was also
achieved (entry 12), at which point the desired product 2a could
be obtained in 95% isolated yield under the optimised conditions.
Longer reaction times were required in the case of electron-rich
phenoxy substrates (2k-m). In the case of the naphthyl analogue
2n, the desired product could only be obtained in 17% isolated
yield, with the majority of the remaining material attributed to
unreacted starting material. This may be due to the steric bulk of
the naphthyl group hindering access to the coupling site.
Pleasingly, compound 2o bearing a pyridine moiety instead of an
aryl was obtained in an excellent yield of 81%.
Table 1. Optimisation of reaction conditions.
The scope of the reaction with respect to the quinoline was also
examined. A methyl group at the C-2 position was well tolerated
(2p). On the aryl backbone, both electron donating -OMe
substituents (2q and 2r) and electron withdrawing -CF3, -F and -
Cl substituents (2s-v) also led to very good yields of product. The
reaction conditions were also applicable to a 4-phenoxy pyridine
substrate.[30] A few quinoline analogues (p-pyridinyl, aldehydic,
and those with an S-linker) failed to cyclise under these
conditions.[31]
mol%
5
O
Pd(OAc)2
O
Base 2
equiv.
Br
Solvent 1.5 mL/mmol
135 °C, Air, 18 h
N
N
2a
1a
Yield by NMR
(%)[a]
Isolated
Yield (%)
Entry]
Base
Solvent
1
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMA
DMF
-
67
70
0
57
-
3
NMP
72
-
4
DMSO
1,4-Dioxane
EtOH
5[b]
6[b]
7[b]
8[b]
9
0
-
0
-
1,2-DCE
MeCN
NMP
0
-
0
-
72
83
39[c]
99
33
-
10
11
12[d]
13[e]
Cs2CO3
NaOtBu
Cs2CO3
Cs2CO3
NMP
-
NMP
-
NMP
95
-
NMP
[a] Yields determined by 1H NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxybenzene as internal standard. [b] Reaction carried out
at the reflux temperature of solvent. [c] Decomposition of starting material
observed. [d] 2 mol% Pd(OAc)2 used. [e] 1 mol% Pd(OAc)2 used.
With optimised conditions in hand, the substrate scope of the
reaction was evaluated (Figure 3). Overall, it was observed that
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10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
R
R
mol%
2
O
O
Pd(OAc)2
Cs2CO3
2
equiv.
Br
R
R
NMP 1.5
mL/mmol
135 °C, Air
N
N
2
1
F
Cl
F
O
O
N
O
O
F
N
N
N
2e
79%
,
h)
2b
2c
2d
93%
,
87%
h)
91%
h)
h)
,
,
(18
(18
(18
(18
O
O
O
O
OCF3
NO2
Cl
CF3
N
N
N
N
2h
90%
h)
2f
2g
,
2i
93%
h)
88%
h)
46%
,
h)
(18
,
,
(20
(18
(18
(18
Me
CO2
O
tBu
O
O
O
OMe
N
,
N
N
N
56%
42% h)[a]
2m
2k
2l
h)
50%
h)
(48
,
2j
h)
,71%
(48
,
(48
O
O
N
O
N
N
N
17%
81%
h)[c]
h)[b]
2p
78%
,
2o
h)
2n
,
,
(30
O
(10
(48
O
O
F
3C
MeO
MeO
h)[c]
N
81%
N
N
h)[c]
Cl
63%
(24
h)
2r
2s
,
,
2q
84%
,
(18
(18
O
O
O
F
N
67%
N
N
2t
2u
2v
68%
,
h)
49%
h)[c]
h)[c]
(24
,
,
F
(24
(48
Figure 3. Substrate scope. All yields are isolated yields.[a] The yield of this product could be improved to 60% when using the following conditions: 5 mol%
Pd(OAc)2, 10 mol% PCy3.HBF4, 2 equiv. Cs2CO3 under N2 at 135 °C for 18 h. [b] The yield of this product could be improved to 66% when using the same
conditions described in [a]. [c] 5 mol% Pd(OAc)2 used.
Compounds containing fused indolquinoline rings are known to
possess antimalarial,[32] antiproliferative and anticancer
activity.[33] Thus, we hoped to access similar compounds by
including this functionality in our substrate scope. A Hartwig-
Buchwald coupling gave the precursor 3 in 74% isolated yield
(Scheme 1). However, when this compound was subjected to
the previously optimised direct arylation conditions given
above, no product was observed. Even when using the
protected (N-Boc) substrate, coupling could not be achieved
under these conditions.[34] We reasoned at this point that
inhibitive N-ligation to palladium could be avoided by the
addition of competitive phosphine ligands.[35] Indeed, when a
new catalytic system of 5 mol% Pd(OAc)2 and 10 mol%
PCy3.HBF4 was employed, the fused product could be
obtained in 83% isolated yield after 3h. An inert atmosphere
was required (Scheme 1).[36]
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10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
Analogues with a hydroxyl group at C-3 can lead to unwanted
agonistic behaviour.[50-51]
mol%
1
Pd
NH2
Br
2(dba)3
mol%
XANTPhos 2.1
Br
HN
N
Cs2CO3 1.5
equiv.
+
Br
N
Dioxane
120 °C, 48 h
74%
3,
O
O
and
inert
P-ligand
required
atmosphere
Br
mol%
mol%
5
Pd(OAc)2
PCy3•HBF4 10
Cs2CO3
NMP, N2
150 °C, 3 h
HN
N
H
C7H15
N
C7H15
2
equiv.
1w
HHQ
N
mol%
2
2
NMP
135 °C, Air, 30 h
Pd(OAc)2
Cs2CO3
83%
4,
equiv.
OH
N
O
Scheme 1. Synthesis and direct arylation of 4-anilinoquinoline substrate.
C7H15
N
H15
C7
The mechanism probably proceeds via an initial oxidative
addition followed by a rate-determing C-H activation via a
concerted metalation deprotonation (CMD).[29,37-40] A CMD
mechanism is often characterised by the acidity of the key C-H
bond. To probe this, a number of competition experiments
were carried out using a basic quinoline substrate 1a and those
substituted with an electron-withdrawing (1s) and an electron-
donating (1q) group (Figure 4 and S.I.). In all cases the
experiment revealed that the electron-poor substrate outpaced
the electron-rich substrate.
Tautomer
Quinoline
2w
70%
,
Figure 5. HHQ-like substrate blocked at C-3.
Thus HHQ was converted into the phenoxy procursor, which
cyclised well, considering the steric encumbrance of the heptyl
chain (the heptyl chain is critical for most biological activity).
The impact of compound 2w on quinolone signalling (more
specifically PqsR signalling) was then investigated. HHQ (and
PQS) are known to act as co-inducer signals of the PqsR LysR-
type transcriptional regulator, leading to transcriptional
activation of the pqsA promoter. Thus, the pqsA promoter itself
acts as a proxy for activation of PqsR signalling. A pqsA fusion
plasmid reporter (pLP0996) contains the pqsA promoter
sequence upstream of the lacZ encoding gene and thus was
ultimately used as indicator.[52] Wild-type P. aeruginosa
produces endogenous HHQ, and thus any interference with
activation of the plasmid encoded pqsA-promoter would likely
infer antagonism of natural co-inducer binding. However, no
such interference was observed and levels of pqsA
transcriptional activation were comparable in carrier and cells
treated with cyclised quinoline 2w (Figure 6). Activation of the
pLP0996 encoded pqsA promoter in a pqsA mutant lacking
endogenous HHQ and PQS can only occur upon addition of
exogenous signal. In this case, while HHQ activated promoter
activity, addition of quinoline 2w had no effect beyond baseline.
Thus quinoline 2w displayed neither agonist nor antagonist
behaviour with respect to PqsR signalling. This was further
evident from the lack of inhibition of pyocyanin production in a
wild-type strain and the lack of pyocyanin restoration in the
pqsA mutant.
O
O
mol%
2
2
Pd(OAc)2
Cs2CO3
NMP
F3C
Br
MeO
Br
equiv.
+
2s
2q
+
°
120
C,
N
1s
N
1q
Air
15 mins
26%
41%
7%
@
@
45 mins
15%
Figure 4. Competition experiment between 1s and 1q.
We then wished to apply the methodology to a more
challenging quinoline of potential biological importance. Many
species of bacteria use a sophisticated communication system
termed ‘quorum sensing’ (QS).[41] This coordinated behaviour
allows for the construction of protective biofilms and the
production of virulence factors, ultimately for the benefit of the
entire colony. In contrast to antibiotic treatment, disrupting QS,
termed ‘quorum quenching’, is non-biocidal and thus as a
strategy, is less likely to promote bacterial resistance by
reducing the level of mutant dominance.[42] Pseudomonas
aeruginosa uses quinolones such as 4-hydroxy-2-
heptylquinoline (HHQ) and its 3-OH analogue Pseudomonas
quinolone signal (PQS) to modulate quorum sensing (Figure
5). Thus analogues of these molecules could be used as
competitive binders, disrupting numerous downstream
processes.
Following on from our continuing investigation of quinolone
and quinoline analogues of HHQ and PQS,[43-49] using
molecules which are ‘blocked’ at the C-3 position, we chose to
apply our intramolecular arylation methodology to a HHQ/PQS
analogue (Figure 5). Substitution of C-3 is often crucial as it
prevents hydroxylation of HHQ at this position by PqsH.
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10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
NMR (400 MHz),1H NMR (300 MHz) spectra were recorded on Bruker
Avance 600, Bruker Avance 500, Bruker Avance 400 and Bruker
Avance 300 NMR spectrometers, respectively, in proton coupled mode
using tetramethysilane (TMS) as the internal standard. 13C NMR (150
MHz), 13C NMR (125 MHz), 13C NMR (100 MHz) and 13C NMR (75
MHz) spectra were recorded on Bruker Avance 600, Bruker Avance
500, Bruker Avance 400 and Bruker Avance 300 NMR spectrometers,
respectively, in proton decoupled mode at 20 °C using tetramethysilane
(TMS) as the internal standard. 19F NMR (282 MHz) spectra were
recorded on a Bruker Avance 300 NMR spectrometer in proton
decoupled mode at 20 °C. 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: 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). High resolution
precise mass spectra (HRMS) were recorded on a Waters LCT Premier
Tof LC-MS instrument in electrospray ionisation (ESI) mode using 50%
acetonitrile-water containing 0.1% formic acid as eluent; samples were
made up in acetonitrile at a concentration of ca. 1 mg/ml. Column
chromatography was carried out using 60 Å (35-70 µm) silica. TLC was
carried out on pre-coated silica gel plates (Merck 60 PF254). The
developed plates were visualized under UV light.
2w
2w
2w
2w
Figure 6. (A) Transcriptional activation of the pqsA promoter was unaffected
in wild-type (PAO1 pMP0996) and mutant (PAO1 pqsA- pLP0996) cells upon
addition of 2w. This suggests that the compound is neither an antagonist nor
an agonist of PqsR signalling under conditions tested. (B) Pyocyanin
production followed a similar pattern, i.e. unaffected in the presence of 2w
in either the wild-type or mutant cells. All data presented is the mean (+/-
SEM) of three independent biological replicates. Statistical analysis was
performed by Students t-test and one way ANOVA with Bonferroni post-hoc
testing (*** p<0.001).
Palladium-catalysed intramolecular direct arylation reactions were
carried out in sealed reaction tubes which were placed in a solid multi-
reaction heating plate.
The production of HHQ-like compounds which do not and
cannot be hydroxylated in vivo at C-3[51] and thus do not exhibit
any strong agonistic or antagonist behaviour, make for an
excellent molecular framework for further modification and
structure-activity studies. Further details of the biological
activity will be published in due course.
General
Procedures
for
Synthesis
of
4-(2-bromophenoxy)quinoline Substrates 1a-1w:
Method (a): compounds 1a-1c, 1f, 1i, 1k, 1l, 1o-1w: A mixture of the
4-chloroquinoline substrate (1 equiv.), the substituted 2-bromophenol
(5 equiv.) and sodium hydroxide (crushed pellets) (1.5 equiv.) was
stirred at 120 °C until reaction was completed (2-6 h) as evident by thin
layer chromatography (hexane/ethyl acetate 8:2). The cooled reaction
mixture was diluted with 10% aq. NaOH (5 mL) and stirred at room
temperature for 1 h. The aqueous phase was extracted with DCM (3 x
20 mL). The combined organic layers were washed with 6M NaOH (3
x 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 hexane/ethyl acetate (8:2) as
eluent.
Conclusions
In summary, the application of direct arylation methodology
towards the synthesis of fused benzofuroquinoline products
has been demonstrated. Placement of the halide on the
phenoxy component of the coupling precursor allows for easy
access to cyclised products. No added phosphine is required
and the reactions can be carried out in air. Modification of the
methodology allows for the inclusion of 4-anilinoquinoline
substrates, without the requirement for N-protection. Finally,
electron-poor quinolines appear to work best as evidenced by
competition experiments. Application to a sterically hindered
(C-2=n-heptyl) HHQ mimic proceeds well.
Method (b): compounds 1d, 1e, 1g, 1h, 1j, 1m, 1n: A mixture of
4-chloroquinoline (1 equiv.), the substituted 2-bromophenol (1.5 equiv.)
and 4-dimethylaminopyridine (3 equiv.) in toluene (1.5 mL/mmol) was
stirred at 130 °C until the reaction was completed as evident by thin
layer chromatography (hexane/ethyl acetate 8:2). The cooled reaction
mixture was diluted with 10% aq. NaOH (5 mL) and stirred at room
temperature for 1 h. The aqueous phase was extracted with DCM (3 x
20 mL). The combined organic layers were washed with 3M NaOH (3
x 10 mL), 1M HCl (2 x 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 hexane/ethyl
acetate (8:2) as eluent.
Experimental Section
General 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.
4-(2-Bromophenoxy)quinoline (1a): Method (a) - white solid (2.89 g,
78%); m.p. = 62-64 °C. IR (film) νmax 3434, 1596, 1305, 1223, 659 cm-1.
1H NMR (300 MHz, CDCl3) δ: 6.41 (d, J = 5.1 Hz, 1H), 7.18-7.27 (m,
2H), 7.43 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 7.61 (ddd, J = 8.2, 6.9, 1.1 Hz,
1H), 7.70-7.82 (m, 2H), 8.12 (d, J = 8.2 Hz, 1H), 8.42 (dd, J = 8.3, 0.9
Infrared spectra were measured on
a
Perkin-Elmer FT-IR
spectrometer. Nuclear Magnetic Resonance (NMR) samples were run
in deuterated chloroform (CDCl3) or deuterated dimethylsulfoxide
(DMSO-d6) as specified. 1H NMR (600 MHz), 1H NMR (500 MHz),1H
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
Hz, 1H), 8.68 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ:
103.7, 116.4, 121.1, 121.9, 123.2, 126.3, 127.3, 129.1, 129.2, 130.2,
134.3, 149.8, 151.0, 151.2, 160.7 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C15H11BrNO: 300.0024; found: 300.0016.
4-(2-Bromo-4-(trifluoromethyl)phenoxy)quinoline (1g): Method (b)
- sticky colourless oil (0.0731 g, 20%). IR (film) νmax 1623, 1569, 1320,
1263, 1231, 1130, 588 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.50 (d, J =
5.1 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.54-7.70 (m, 2H), 7.79 (ddd, J =
8.4, 6.9, 1.4 Hz, 1H), 8.00 (d, J = 1.7 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H),
8.34 (dd, J = 8.4, 0.9 Hz, 1H), 8.73 (d, J = 4.9 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3) δ: 104.7, 116.5, 121.0, 121.7, 122.6, 122.9 (q, 1J(C,F)
= 272 Hz), 126.4 (q, J(C,F) = 4 Hz), 126.7, 129.2 (q, J(C,F) = 34 Hz),
129.3, 130.5, 131.7 (q, 3J(C,F) = 4 Hz), 150.0, 150.9, 154.4, 159.8 ppm.
19F NMR (282 MHz, CDCl3) δ: -62 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C16H10BrF3NO: 367.9898; found: 367.9886.
4-(2-Bromo-5-fluorophenoxy)quinoline (1b): Method (a)
- pale
yellow solid (0.891 g, 91%); m.p. = 77-78 °C. IR (film) νmax 3066, 1476,
1305, 1252, 1159, 601 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.49 (d, J =
5.1 Hz, 1H), 6.94-7.01 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 7.57-7.74 (m,
2H), 7.80 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.37
(dd, J = 8.4, 1.0 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75
MHz, CDCl3) δ: 104.1, 110.7, 110.9 (d, 2J(C,F) = 25 Hz), 114.5 (d, 2J(C,F)
3
2
3
= 22 Hz), 120.9, 121.7, 126.5, 129.2, 130.4, 134.7 (d, J(C,F) = 9 Hz),
4-(2-Bromo-4-(trifluoromethoxy)phenoxy)quinoline (1h): Method
(b) - pale yellow solid (0.3015 g, 78%); m.p. 50-52 °C. IR (film) νmax
1640, 1597, 1306, 1253, 1218, 1187, 567 cm-1. 1H NMR (300 MHz,
CDCl3) δ: 6.44 (d, J = 5.1 Hz, 1H), 7.22-7.35 (m, 2H), 7.55-7.69 (m,
2H), 7.79 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.38
(dd, J = 8.4, 0.9 Hz, 1H), 8.71 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75
MHz, CDCl3) δ: 103.8, 116.9, 120.4 (q, 1J(C,F) = 259 Hz), 120.9, 121.7,
121.8, 123.7, 126.5, 127.0, 129.2, 130.4, 146.6, 149.9, 150.0, 151.0,
160.3 ppm. 19F NMR (282 MHz, CDCl3) δ: -58 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C16H10BrF3NO2: 383.9847; found: 383.9843.
149.9, 151.0, 152.0 (d, 3J(C,F) = 11 Hz), 160.1, 162.4 (d, 1J(C,F) = 250 Hz)
ppm. 19F NMR (282 MHz, CDCl3) δ: -111 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C15H10BrFNO: 317.9930; found: 317.9936.
4-(2-Bromo-4-fluorophenoxy)quinoline (1c): Method (a)
- pale
yellow solid (0.188 g, 38%); m.p. = 100-103 °C. IR (film) νmax 3065,
1480, 1305, 1248, 1183, 765 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.39
(d, J = 5.1 Hz, 1H), 7.10-7.29 (m, 2H), 7.48 (dd, J = 7.7, 2.8 Hz, 1H),
7.62 (ddd, J = 8.2, 5.5, 1.2 Hz, 1H), 7.79 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H),
8.12 (d, J = 8.5 Hz, 1H), 8.40 (dd, J = 8.3, 0.9 Hz, 1H), 8.69 (d, J = 5.1
Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 103.4, 116.1 (d, 2J(C,F) = 23
Hz), 116.9 (d, 3J(C,F) = 10 Hz), 120.9, 121.3 (d, 2J(C,F) = 26 Hz), 121.8,
124.3 (d, 3J(C,F) = 9 Hz), 126.4, 129.2, 130.3, 147.4, 149.8, 151.0, 159.9
4-(2-Bromo-4-nitrophenoxy)quinoline (1i): Method (a) - pale yellow
solid (0.192 g, 80%); m.p. = 151-152 °C. IR (film) νmax 3376, 1523,
1346, 1305, 1257, 665 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.65 (d, J =
5.0 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 7.64 (ddd, J = 8.1, 7.1, 0.7 Hz,
1H), 7.83 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.25
(d, J = 8.8 Hz, 1H), 8.27 (dd, J = 8.9, 2.7 Hz, 1H), 8.65 (d, J = 2.6 Hz,
1H), 8.80 (d, J = 5.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 106.0,
115.9, 121.1, 121.2, 121.5, 124.6, 127.1, 129.5, 129.9, 130.7, 144.9,
150.2, 151.0, 157.2, 159.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H10BrN2O3: 344.9875; found: 344.9865.
1
(d, J(C,F) = 250 Hz), 160.7 ppm. 19F NMR (282 MHz, CDCl3) δ: -114
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C15H10BrFNO: 317.9930;
found: 317.9935.
4-(2-Bromo-6-fluorophenoxy)quinoline (1d): Method (b)
- pale
yellow solid (0.318 g, 72%); m.p. = 118-119 °C. IR (film) νmax 3064,
1502, 1471, 1305, 1271, 1042, 665 cm-1. 1H NMR (300 MHz, CDCl3) δ:
6.39 (d, J = 5.1 Hz, 1H), 7.15-7.30 (m, 2H), 7.47-7.54 (m, 1H), 7.63
(ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.79 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 8.13
(d, J = 8.5 Hz, 1H), 8.46 (dd, J = 8.3, 1.1 Hz, 1H), 8.69 (d, J = 5.0 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 102.5, 116.5 (d, 2J(C,F) = 19 Hz),
Methyl 4-bromo-3-(quinolin-4-yloxy)benzoate (1j): Method (b) - off
white solid (0.258 g, 62%); m.p. = 87-89 °C. IR (film) νmax 3586, 2950,
1724, 1565, 1502, 1392, 1294, 1241, 765 cm-1. 1H NMR (300 MHz,
CDCl3) δ: 3.92 (s, 3H), 6.43 (d, J = 5.1 Hz, 1H), 7.63 (ddd, J = 8.2, 6.9,
1.1 Hz, 1H), 7.76-7.90 (m, 4H), 8.13 (d, J = 8.5 Hz, 1H), 8.40 (dd, J =
8.3, 0.9 Hz, 1H), 8.70 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3) δ: 52.6, 103.9, 121.0, 121.7, 122.0, 123.9, 126.5, 128.0, 129.2,
130.4, 131.6, 134.5, 149.9, 151.0, 151.4, 160.3, 165.4 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C17H13BrNO3: 358.0079; found:
358.0089.
3
118.3, 120.6, 121.9, 126.4, 127.7 (d, J(C,F) = 8 Hz), 129.10, 129.16,
2
1
130.2, 139.3 (d, J(C,F) = 14 Hz), 149.8, 150.9, 155.6 (d, J(C,F) = 255
Hz), 159.8 ppm. 19F NMR (282 MHz, CDCl3) δ: -124 ppm. HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for C15H10BrFNO: 317.9930; found: 317.9921.
4-(2-Bromo-5-chlorophenoxy)quinoline (1e): Method (b) - white
solid (0.290 g, 89%); m.p. = 79-81 °C. IR (film) νmax 3370, 1562, 1464,
1305, 1252, 765, 665 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.48 (d, J =
5.1 Hz, 1H), 7.16-7.29 (m, 2H), 7.57-7.69 (m, 2H), 7.79 (ddd, J = 8.5,
6.9, 1.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.36 (dd, J = 8.4, 0.9 Hz, 1H),
8.72 (d, J = 5.1 Hz, 1H) ppm.13C NMR (75 MHz, CDCl3) δ: 104.1, 114.4,
120.9, 121.7, 123.3, 126.5, 127.4, 129.2, 130.4, 134.5, 134.8, 149.9,
151.0, 151.9, 160.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
4-(2-Bromo-4-methylphenoxy)quinoline (1k): Method (a) - orange
solid (0.242 g, 84%); m.p. = 122-125 °C. IR (film) νmax 3064, 1568,
1485, 1392, 1255, 765 cm-1. 1H NMR (300 MHz, CDCl3) δ: 2.41 (s, 3H),
6.40 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 8.2, 1.5
Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H),
7.78 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.43 (dd,
J = 8.3, 1.0 Hz, 1H), 8.67 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3) δ: 20.7, 103.5, 115.9, 121.1, 121.9, 122.9, 126.2, 129.1, 129.8,
130.1, 134.5, 137.5, 148.8, 149.8, 151.0, 161.0 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C16H13Br NO: 314.0181; found: 314.0169.
C15H10BrClNO: 333.9634; found: 333.9622.
4-(2-Bromo-4-chlorophenoxy)quinoline (1f): Method (a) - off-white
solid (1.97 g, 96%); m.p. = 112-115 °C. IR (film) νmax 3403, 1596, 1465,
1392, 1257, 824, 765 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.42 (d, J =
5.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 8.7, 2.5 Hz, 1H),
7.61 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.70-7.84 (m, 2H), 8.12 (d, J = 8.5
Hz, 1H), 8.38 (dd, J = 8.4, 0.9 Hz, 1H), 8.70 (d, J = 5.1 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3) δ: 103.7, 117.0, 120.9, 121.7, 123.8, 126.4,
129.2, 129.3, 130.3, 132.0, 133.9, 149.9, 150.0, 151.0, 160.4 ppm.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C15H10BrClNO: 333.9634;
found: 333.9629.
4-(2-Bromo-4-(tert-butyl)phenoxy)quinoline (1l): Method (a) - pale
yellow solid (0.073 g, 56%); m.p. = 68-70 °C. IR (film) νmax 2963, 1568,
1488, 1391, 1306, 1263, 766 cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.36
(s, 9H), 6.43 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.41 (dd, J =
8.5, 2.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.65-7.83 (m, 2H), 8.11 (d, J
= 8.5 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.67 (d, J = 5.0 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3) δ: 31.3, 34.7, 103.6, 115.8, 121.1, 121.9,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
122.6, 126.2, 126.3, 129.0, 130.2, 131.2, 148.5, 149.7, 150.9, 151.1,
160.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C19H19BrNO:
356.0650; found: 356.0642.
ppm. 13C NMR (75 MHz, CDCl3) δ: 55.5, 102.4, 107.3, 115.8, 116.3,
119.2, 123.1, 123.2, 127.1, 129.1, 134.2, 151.2, 151.5, 151.8, 160.7,
161.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C16H12BrNO2:
330.0130; found: 330.0128.
4-(2-Bromo-4-methoxyphenoxy)quinoline (1m): Method (b) - beige
solid (0.304 g, 56%); m.p. = 184-185 °C. IR (film) νmax 3062, 2835,
1595, 1487, 1392, 1212, 765 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.86
(s, 3H), 6.38 (d, J = 5.2 Hz, 1H), 6.96 (dd, J = 8.9, 2.9 Hz, 1H), 7.17 (d,
J = 8.9 Hz, 1H), 7.24 (d, J = 2.9 Hz, 1H), 7.60 (ddd, J = 8.1, 6.9, 1.1 Hz,
1H), 7.77 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.43
(dd, J = 8.3, 0.9 Hz, 1H), 8.67 (d, J = 5.0 Hz, 1H) ppm. 13C NMR (75
MHz, CDCl3) δ: 55.9, 103.3, 114.9, 116.7, 118.9, 121.0, 121.9, 123.7,
126.2, 129.0, 130.1, 144.5, 149.7, 151.0, 157.9, 161.3 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C16H13BrNO2: 330.0130; found:
330.0125.
4-(2-Bromophenoxy)-6-(trifluoromethyl)quinoline (1s): Method (a) -
off-white solid (0.254 g, 80%); m.p. = 67-69 °C. IR (film) νmax 3069,
1570, 1467, 1316, 1224, 1126, 739 cm-1. 1H NMR (300 MHz, CDCl3) δ:
6.47 (d, J = 5.2 Hz, 1H), 7.21-7.32 (m, 2H), 7.46 (ddd, J = 8.1, 7.3, 1.6
Hz, 1H), 7.75 (dd, J = 7.9, 1.3 Hz, 1H), 7.95 (dd, J = 8.9, 2.1 Hz, 1H),
8.22 (d, J = 8.9 Hz, 1H), 8.76 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H) ppm. 13
C
NMR (125 MHz, CDCl3) δ: 104.4, 116.4, 120.2, 120.3 (q, 3J(C,F) = 5 Hz),
123.4, 124.1 (q, 1J(C,F) = 272 Hz), 126.0 (q, 3J(C,F) = 3 Hz), 127.8, 128.2
(q, 2J(C,F) = 33 Hz), 129.4, 130.3, 134.5, 150.6, 150.7, 153.2, 161.3 ppm.
19F NMR (282 MHz, CDCl3) δ: -62 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C16H10BrF3NO: 367.9898; found: 367.9894.
4-((1-Bromonaphthalen-2-yl)oxy)quinoline (1n): Method (a) - off-
white solid (0.318 g, 61%); m.p. = 197-200 °C. IR (film) νmax 3062, 1594,
1568, 1499, 1392, 1253, 764 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.42
(d, J = 5.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.55-7.72 (m, 3H), 7.80
(ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.8
Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.51 (dd, J
= 8.3, 1.0 Hz, 1H), 8.56 (d, J = 5.1 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3) δ: 103.9, 115.2, 121.1, 121.3, 122.0, 126.3, 126.6, 127.1, 128.2,
128.4, 129.1, 129.8, 130.3, 132.4, 133.2, 149.0, 149.8, 151.1, 160.8
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C19H13BrNO: 350.0181;
found: 350.0178.
4-(2-Bromophenoxy)-6-fluoroquinoline (1t): Method (a) - pale yellow
solid (0.344 g, 65%); m.p. = 75-79 °C. IR (film) νmax 3422, 1630, 1262,
1222, 1177, 657 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.43 (d, J = 5.1
Hz, 1H), 7.19-7.24 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.44 (t, J = 7.4 Hz,
1H), 7.54 (td, J = 8.7, 2.8 Hz, 1H), 7.73 (d, J = 9.9 Hz, 1H), 8.02 (dd, J
= 9.3, 2.8 Hz, 1H), 8.12 (dd, J = 9.2, 5.2 Hz, 1H), 8.64 (d, J = 5.1 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 104.0, 105.7 (d, 2J(C,F) = 24 Hz),
116.3, 120.4 (d, 2J(C,F) = 26 Hz), 121.7 (d, 3J(C,F) = 10 Hz), 123.3, 127.5,
129.3, 131.7 (d, 3J(C,F) = 10 Hz), 134.4, 146.9, 150.3 (d, 6J(C,F) = 3 Hz),
150.8, 160.3 (d, 4J(C,F) = 5 Hz), 160.4 (d, 1J(C,F) = 248 Hz) ppm. 19F NMR
(282 MHz, CDCl3) δ: -113 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H10BrFNO: 317.9930; found: 317.9917.
4-((2-Bromopyridin-3-yl)oxy)quinoline (1o): Method (a) - pale pink
solid (0.2378 g, 79%); m.p. 170-173 °C. IR (film) νmax 1639, 1503, 1305,
1268, 666 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.45 (d, J = 5.1 Hz, 1H),
7.38 (dd, J = 8.0, 4.6 Hz, 1H), 7.47-7.70 (m, 2H), 7.79 (ddd, J = 8.4,
7.0, 1.4 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.28-8.47 (m, 2H), 8.72 (d, J
= 5.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 104.1, 121.0, 121.7,
124.0, 126.7, 129.2, 130.5, 130.5, 136.6, 147.0, 148.7, 149.9, 150.8,
159.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C14H10BrN2O:
300.9976; found: 300.9986.
4-(2-Bromophenoxy)-8-fluoroquinoline (1u): Method (a)
- pale
yellow crystalline solid (0.2519 g, 53%); m.p. 87-90 °C. IR (film) νmax
1631, 1597, 1264, 1224, 949, 612 cm-1. 1H NMR (300 MHz, CDCl3) δ:
6.45 (d, J = 5.1 Hz, 1H), 7.12-7.29 (m, 2H), 7.34-7.58 (m, 3H), 7.70 (dd,
J = 8.0, 1.4 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.71 (d, J = 5.1 Hz, 1H)
4
ppm. 13C NMR (75 MHz, CDCl3) δ: 104.4, 114.3 (d, J(C,F) = 19 Hz),
116.2, 117.7 (d, 4J(C,F) = 5 Hz), 122.7 (d, 3J(C,F) = 3 Hz), 123.2, 126.0 (d,
2
3J(C,F) = 8 Hz), 127.55, 129.3, 134.3, 140.0 (d, J(C,F) = 13 Hz), 150.7,
151.2, 157.9 (d, 1J(C,F) = 256 Hz), 160.6 (d, 4J(C,F) = 4 Hz) ppm. 19F NMR
(282 MHz, CDCl3) δ: -125 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H10BrFNO: 317.9930; found: 317.9918.
4-(2-Bromophenoxy)-2-methylquinoline (1p): Method (a) - pale pink
solid (0.331 g, 93%); m.p. = 98-101 °C. IR (film) νmax 2923, 1599, 1470,
1342, 1235, 754 cm-1. 1H NMR (300 MHz, CDCl3) δ: 2.60 (s, 3H), 6.29
(s, 1H), 7.15-7.29 (m, 2H), 7.42 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.54
(ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.68-7.79 (m, 2H), 8.02 (d, J = 8.4 Hz,
1H), 8.35 (dd, J = 8.4, 1.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ:
25.8, 104.2, 116.3, 119.5, 121.7, 123.2, 125.4, 127.1, 128.3, 129.1,
130.2, 134.3, 149.4, 151.3, 159.9, 160.8 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C16H13BrNO: 314.0181; found: 314.0179.
4-(2-Bromophenoxy)-6-chloroquinoline (1v): Method (a) - off-white
solid (0.4525 g, 90%); m.p. 89-90 °C. IR (film) νmax 1642, 1563, 1262,
1222, 666, 643 cm-1. 1H NMR (300 MHz, CDCl3) δ: 6.41 (d, J = 5.2 Hz,
1H), 7.17-7.30 (m, 2H), 7.44 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.65-7.69
(m, 2H), 8.04 (d, J = 9.0 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.66 (d, J =
5.2 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 104.2, 116.3, 121.0,
121.6, 123.2, 127.5, 129.3, 130.8, 131.1, 132.2, 134.3, 148.1, 150.7,
151.2, 160.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
4-(2-Bromophenoxy)-6-methoxyquinoline (1q): Method (a) - yellow
sticky oil (0.599 g, 70%); IR (film) νmax 3392, 1596, 1467, 1365, 1262,
1223, 778 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.98 (s, 3H), 6.40 (d, J =
5.1 Hz, 1H), 7.16-7.29 (m, 2H), 7.37-7.47 (m, 2H), 7.64 (d, J = 2.8 Hz,
1H), 7.73 (dd, J = 8.0, 1.5 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.54 (d, J
= 5.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 55.7, 99.4, 104.2,
116.4, 121.8, 122.9, 123.2, 127.2, 129.2, 130.7, 134.3, 145.9, 148.4,
151.3, 157.8, 159.7 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C15H10BrClNO: 333.9634; found: 333.9628.
4-(2-Bromophenoxy)-2-heptylquinoline (1w): Method (a) - off-white
solid (0.205 g, 90%); m.p. = 75-77 °C. IR (film) νmax 2926, 2855, 1600,
1470, 1359, 1234, 763 cm-1. 1H NMR (300 MHz, CDCl3) δ: 0.85 (t, J =
6.7 Hz, 3H), 1.14-1.42 (m, 8H), 1.68 (m, 2H), 2.80 (t, J = 8.1 Hz, 2H),
6.30 (s, 1H), 7.17-7.25 (m, 2H), 7.42 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H),
7.53 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.63-7.81 (m, 2H), 8.05 (d, J = 8.4
Hz, 1H), 8.34 (dd, J = 8.3, 0.9 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3)
δ: 14.1, 22.6, 29.2, 29.4, 30.0, 31.8, 39.7, 103.8, 116.3, 119.7, 121.7,
123.1, 125.4, 127.1, 128.5, 129.2, 130.1, 134.3, 149.5, 151.4, 160.7,
164.2 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C22H25BrNO:
398.1120; found: 398.1135.
C16H13BrNO2: 330.0130; found: 330.0130.
4-(2-Bromophenoxy)-7-methoxyquinoline (1r): Method (a) - pale
yellow solid (0.380 g, 74%); m.p. = 99-100 °C. IR (film) νmax 3388, 1622,
1428, 1315, 1227, 665 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.98 (s, 3H),
6.30 (d, J = 5.2 Hz, 1H), 7.15-7.29 (m, 3H), 7.36-7.47 (m, 2H), 7.72 (dd,
J = 7.9, 1.5 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
General Procedure for Palladium-Catalysed Intramolecular Direct
Arylation Reactions for the Preparation of Compounds 2a-2w: A
mixture of the 4-(2-bromophenoxy)quinoline substrate 1 (1 equiv.),
Pd(OAc)2 (2-5 mol%), and anhydrous caesium carbonate (2 equiv.) in
anhydrous N-methylpyrrolidone (1.5 mL/mmol) was stirred at 135 °C in
a sealed reaction tube until the reaction was completed as evident by
1H 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 eluent.
144.1, 147.5, 156.0, 157.8 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H9ClNO: 254.0373; found: 254.0363.
8-Chlorobenzofuro[3,2-c]quinoline (2f):[27] White solid (0.071 g,
93%); m.p. = 187-189 °C (lit.[27] 189-190 °C). IR (film) νmax 2917, 1564,
1511, 1395, 1194, 871 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.51 (dd, J
= 8.8, 2.2 Hz, 1H), 7.69 (dd, J = 8.8, 0.4 Hz, 1H), 7.72 (ddd, J = 8.1,
7.0, 1.2 Hz, 1H), 7.82 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 8.08 (dd, J = 2.2,
0.4 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.41 (dd, J = 8.2, 0.9 Hz, 1H),
9.46 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ: 113.1, 115.5, 117.0,
120.5, 120.8, 124.1, 127.28, 127.34, 129.75, 129.78, 130.0, 144.2,
147.6, 154.2, 158.2 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
Benzofuro[3,2-c]quinoline (2a):[27] White solid (0.068 g, 95%); m.p. =
132-135 °C (lit.[27] 135-138 °C). IR (film) νmax 3369, 1566, 1510, 1399,
1190 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.44-7.58 (m, 2H), 7.65-7.83
(m, 3H), 8.12 (dd, J = 7.2, 0.9 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.44
(dd, J = 8.1, 1.0 Hz, 1H), 9.51 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3)
δ: 112.1, 116.3, 117.2, 120.6, 120.8, 122.7, 124.1, 127.0, 127.2, 129.3,
129.9, 144.4, 147.4, 156.0, 157.5 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C15H10NO: 220.0762; found: 220.0755.
C15H9ClNO: 254.0373; found: 254.0370.
8-(Trifluoromethyl)benzofuro[3,2-c]quinoline (2g): White crystalline
solid (0.0533 g, 88%); m.p. 170-173 °C. IR (film) νmax 1627, 1567, 1333,
1310, 1151, 1110 cm-1. 1H NMR (400 MHz, CDCl3) δ: 7.65-7.91 (m,
4H), 8.29 (d, J = 8.5 Hz, 1H), 8.35-8.48 (m, 2H), 9.52 (s, 1H) ppm. 13
C
NMR (75 MHz, CDCl3) δ: 112.5, 115.4, 116.8, 118.3 (q, 3J(C,F) = 4 Hz),
120.7, 123.0, 124.3 (q, 3J(C,F) = 4 Hz), 124.3 (q, 1J(C,F) = 272 Hz), 126.8
(q, 2J(C,F) = 33 Hz), 127.4, 129.9, 130.0, 144.1, 147.8, 157.2, 158.4 ppm.
19F NMR (282 MHz, CDCl3) δ: -61 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C16H9F3NO: 288.0636; found: 288.0629.
9-Fluorobenzofuro[3,2-c]quinoline (2b):[53] White solid (0.064 g,
88%); m.p. = 149-150 °C (lit.[53] 148-150 °C). IR (film) νmax 3052, 1564,
1512, 1396, 1254, 1134 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.22 (ddd,
J = 8.9, 6.9, 2.2 Hz, 1H), 7.45 (dd, J = 8.6, 2.2 Hz, 1H), 7.63-7.85 (m,
2H), 8.00 (dd, J = 8.6, 5.3 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.36 (dd, J
= 8.1, 1.1 Hz, 1H), 9.43 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ:
100.3 (d, 2J(C,F) = 27 Hz), 112.3 (d, 2J(C,F) = 24 Hz), 115.8, 117.0, 118.9
(d, 4J(C,F) = 2 Hz), 120.6, 121.2 (d, 3J(C,F) = 10 Hz), 127.2, 129.4, 129.8,
143.9, 147.1, 156.1 (d, 3J(C,F) = 14 Hz), 158.1 (d, 5J(C,F) = 3 Hz), 162.2
8-(Trifluoromethoxy)benzofuro[3,2-c]quinoline
(2h):
White
crystalline solid (0.1367 g, 90%); m.p. 124-126 °C. IR (film) νmax 1641,
1512, 1280, 1247, 1206, 1141, 1156 cm-1. 1H NMR (300 MHz, CDCl3)
δ: 7.41 (ddd, J = 8.9, 2.4, 0.8 Hz, 1H), 7.64-7.88 (m, 3H), 7.95 (d, J =
1.1 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.41 (dd, J = 8.1, 1.0 Hz, 1H),
9.47 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 113.0, 113.6, 115.9,
1
(d, J(C,F) = 247 Hz) ppm. 19F NMR (282 MHz, CDCl3) δ: -112 ppm.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C15H9FNO: 238.0668; found:
1
117.0, 120.6 (q, J(C,F) = 257 Hz), 120.7, 120.8, 123.8, 127.4, 129.9,
130.0, 144.2, 145.8, 147.8, 153.9, 158.7 ppm. 19F NMR (282 MHz,
238.0668.
CDCl3) δ: -58 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
8-Fluorobenzofuro[3,2-c]quinoline (2c):[27] White solid (0.087 g,
91%); m.p. = 163-164 °C (lit.[27] 162-163 °C). IR (film) νmax 3368, 1565,
1479, 1319, 1247, 1146 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.21-7.33
(m, 1H), 7.65-7.87 (m, 4H), 8.28 (d, J = 8.4 Hz, 1H), 8.41 (dd, J = 8.1,
1.0 Hz, 1H), 9.45 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 106.7 (d,
2J(C,F) = 26 Hz), 112.9 (d, 3J(C,F) = 9 Hz), 114.7 (d, 2J(C,F) = 26 Hz), 116.1
(d, 4J(C,F) = 4 Hz), 117.0, 120.8, 123.6 (d, 3J(C,F) = 11 Hz), 127.2, 129.6,
C16H9F3NO2: 304.0585; found: 304.0574.
8-Nitrobenzofuro[3,2-c]quinoline (2i): Orange solid (0.028 g, 46%);
m.p. >250 °C. IR (film) νmax 3030, 1528, 1397, 1344, 1200 cm-1. 1H
NMR (300 MHz, CDCl3) δ: 7.77 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H), 7.84-
7.91 (m, 2H), 8.32 (d, J = 8.5 Hz, 1H), 8.41-8.52 (m, 2H), 9.02 (d, J =
2.3 Hz, 1H), 9.56 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ: 112.6,
115.4, 116.8, 117.1, 120.8, 123.0, 123.6, 127.8, 130.1, 130.5, 144.1,
144.9, 148.1, 158.6, 159.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H9N2O3: 265.0613; found: 265.0611.
129.9, 144.2, 147.5, 151.9, 158.6, 159.7 (d, 1J(C,F) = 241 Hz) ppm. 19
F
NMR (282 MHz, CDCl3) δ: -118 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C15H9FNO: 238.0668; found: 238.0659.
10-Fluorobenzofuro[3,2-c]quinoline (2d):[27] White solid (0.104 g,
93%); m.p. = 156-157 °C (lit.[27] 157-158 °C). IR (film) νmax 3368, 1564,
1496, 1347, 1200, 1189 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.27-7.35
(m, 1H), 7.42 (td, J = 8.0, 4.4 Hz, 1H), 7.73 (ddd, J = 8.1, 7.0, 1.2 Hz,
1H), 7.79-7.92 (m, 2H), 8.29 (d, J = 8.2 Hz, 1H), 8.49 (dd, J = 8.1, 0.9
Hz, 1H), 9.50 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 113.7 (d, 2J(C,F)
= 16 Hz), 116.0, 116.1 (d, 4J(C,F) = 4 Hz), 117.0, 120.8, 124.8 (d, 3J(C,F)
Methyl benzofuro[3,2-c]quinoline-9-carboxylate (2j): Beige solid
(0.043 g, 56%); m.p. = 192-193 °C. IR (film) νmax 3402, 1717, 1565,
1434, 1397, 1281, 1234 cm-1. 1H NMR (300 MHz, CDCl3) δ: 4.00 (s,
3H), 7.70 (m, 1H), 7.81 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 8.09 (d, J = 7.8
Hz, 1H), 8.16 (dd, J = 8.2, 1.3 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.36-
8.43 (m, 2H), 9.46 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 52.5,
113.6, 115.5, 116.9, 120.2, 121.0, 125.5, 126.8, 127.3, 129.0, 129.9,
130.0, 144.5, 147.8, 155.4, 159.0, 166.6 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C17H12NO3: 278.0817; found: 278.0811.
= 6 Hz), 126.2 (d, 3J(C,F) = 3 Hz), 127.3, 129.7, 129.8, 142.7 (d, 2J(C,F)
=
11 Hz), 144.3, 147.7, 148.3 (d, 1J(C,F) = 251 Hz), 157.8 ppm. 19F NMR
(282 MHz, CDCl3) δ: -135 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H9FNO: 238.0668; found: 238.0662.
8-Methylbenzofuro[3,2-c]quinoline (2k):[27] White solid (0.062 g,
71%); m.p. = 145-148 °C (lit.[27] 149-150 °C). IR (film) νmax 2917, 1564,
1510, 1321, 1192 cm-1. 1H NMR (300 MHz, CDCl3) δ: 2.57 (s, 3H), 7.35
(ddd, J = 8.5, 1.8, 0.5 Hz, 1H), 7.61-7.73 (m, 2H), 7.78 (ddd, J = 8.5,
6.9, 1.6 Hz, 1H), 7.89-7.92 (m, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.41 (dd,
J = 8.1, 0.9 Hz, 1H), 9.47 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ:
21.4, 111.5, 116.2, 117.2, 120.5, 120.8, 122.6, 126.8, 128.3, 129.1,
129.8, 133.7, 144.3, 147.3, 154.3, 157.6 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C16H12NO: 234.0919; found: 234.0921.
9-Chlorobenzofuro[3,2-c]quinoline (2e): White solid (0.086 g, 79%);
m.p. = 198-199 °C. IR (film) νmax 3047, 1562, 1508, 1338, 1049, 755
cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.47 (dd, J = 8.3, 1.8 Hz, 1H), 7.66-
7.87 (m, 3H), 8.00 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.40 (d,
J = 8.0 Hz, 1H), 9.46 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 112.8,
115.7, 117.0, 120.7, 121.1, 121.4, 124.8, 127.2, 129.6, 129.9, 132.9,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
8-(tert-Butyl)benzofuro[3,2-c]quinoline (2l):[27] Pale yellow solid
(0.025 g, 50%); m.p. = 97-100 °C (lit.[27] 99-100 °C). IR (film) νmax 2962,
1567, 1488, 1392, 1201 cm-1. 1H NMR (600 MHz, CDCl3) δ: 1.47 (s,
9H), 7.61 (dd, J = 8.7, 2.0 Hz, 1H), 7.67-7.72 (m, 2H), 7.79 (ddd, J =
8.4, 6.9, 1.5 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H),
8.42 (dd, J = 8.2, 1.0 Hz, 1H), 9.52 (s, 1H) ppm. 13C NMR (150 MHz,
CDCl3) δ: 31.9, 35.0, 111.4, 116.7, 116.9, 117.3, 120.8, 122.3, 125.1,
126.9, 129.2, 129.8, 144.4, 147.3, 147.4, 154.2, 157.8 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C19H18NO: 276.1388; found:
276.1377.
1242, 1168 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.97 (s, 3H), 7.31 (dd,
J = 9.0, 2.3 Hz, 1H), 7.36-7.54 (m, 2H), 7.58 (d, J = 2.3 Hz, 1H), 7.68
(d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H),
9.37 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 55.5, 108.4, 111.7,
112.0, 115.0, 119.7, 120.3, 121.9, 122.8, 123.9, 126.7, 144.6, 149.3,
155.8, 157.8, 160.7 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C16H12NO2: 250.0868; found: 250.0865.
2-(Trifluoromethyl)benzofuro[3,2-c]quinoline (2s): Yellow solid
(0.049 g, 63%); m.p. = 141-143 °C. IR (film) νmax 2917, 1567, 1443,
1348, 1167, 1111 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.43-7.67 (m,
2H), 7.80 (d, J = 8.2 Hz, 1H), 7.96 (dd, J = 9.0, 2.0 Hz, 1H), 8.13 (d, J
= 8.4 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.75 (s, 1H), 9.60 (s, 1H) ppm.
13C NMR (100 MHz, CDCl3) δ: 112.3, 116.3, 117.3, 119.1 (q, 3J(C,F) = 5
8-Methoxybenzofuro[3,2-c]quinoline (2m):[28] Off-white solid (0.032
g, 42%); m.p. = 165-167 °C (lit.[28] 160-162 °C). IR (film) νmax 3350,
1570, 1486, 1330, 1186, 1164 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.96
(s, 3H), 7.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.59-
7.85 (m, 3H), 8.26 (d, J = 8.4 Hz, 1H), 8.40 (dd, J = 8.1, 1.0 Hz, 1H),
9.46 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 56.1, 103.3, 112.6,
115.5, 116.6, 117.3, 120.8, 123.3, 127.0, 129.3, 129.8, 144.4, 147.3,
150.7, 156.9, 158.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
Hz), 120.8, 122.1, 124.3 (q, 1J(C,F) = 270 Hz), 124.5, 124.9 (q, 3J(C,F)
=
2
3 Hz), 127.9, 128.8 (q, J(C,F) = 33 Hz), 131.0, 146.4, 148.0, 156.1,
157.5 ppm. 19F NMR (282 MHz, CDCl3) δ: -62 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C16H9F3NO: 288.0636; found: 288.0634.
2-Fluorobenzofuro[3,2-c]quinoline (2t):[53] White solid (0.025 g,
67%); m.p. = 146-148 °C (lit.[53] 148-149 °C). IR (film) νmax 3399, 1515,
1462, 1364, 1195, 1175 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.45-7.61
(m, 3H), 7.76 (d, J = 8.1 Hz, 1H), 8.00 (dd, J = 8.6, 2.8 Hz, 1H), 8.10
(dd, J = 7.6, 0.8 Hz, 1H), 8.26 (dd, J = 9.3, 5.2 Hz, 1H), 9.45 (s, 1H)
C
16H12NO2: 250.0868; found: 250.0858.
Naphtho[1',2':4,5]furo[3,2-c]quinoline (2n): Off-white solid (0.014 g,
17%); m.p. = 203-205 °C. IR (film) νmax 2919, 1562, 1507, 1310, 1223
cm-1. 1H NMR (600 MHz, CDCl3) δ: 7.64 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H),
7.75 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.79-7.85 (m, 2H), 7.94 (d, J = 8.9
Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.33 (d, J =
8.4 Hz, 1H), 8.51 (dd, J = 8.4, 1.1 Hz, 1H), 8.69 (d, J = 8.2 Hz, 1H),
9.97 (s, 1H) ppm. 13C NMR (150 MHz, CDCl3) δ: 112.7, 117.0, 117.3,
117.7, 120.7, 124.2, 125.3, 127.2, 127.7, 128.5, 128.8, 129.2, 129.4,
129.8, 131.0, 145.1, 146.4, 154.1, 157.0 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C19H12NO: 270.0919; found: 270.0916.
2
ppm. 13C NMR (75 MHz, CDCl3) δ: 104.7 (d, J(C,F) = 24 Hz), 112.2,
116.8, 117.8 (d, 3J(C,F) = 11 Hz), 119.3 (d, 2J(C,F) = 26 Hz), 120.8, 122.5,
3
6
124.2, 127.6, 132.5 (d, J(C,F) = 9 Hz), 143.6 (d, J(C,F) = 3 Hz), 144.4,
156.1, 157.1 (d, 4J(C,F) = 5 Hz), 160.8 (d, 1J(C,F) = 249 Hz) ppm. 19F NMR
(282 MHz, CDCl3) δ: -111 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for C15H9FNO: 238.0668; found: 238.0659.
4-Fluorobenzofuro[3,2-c]quinoline (2u): White crystalline solid
(0.0405 g, 49%); m.p. 153-155 °C. IR (film) νmax 1640, 1596, 1300,
1249, 949 cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.40-7.68 (m, 4H), 7.75
(d, J = 8.1 Hz, 1H), 7.99-8.27 (m, 2H), 9.53 (s, 1H) ppm. 13C NMR (100
Pyrido[2',3':4,5]furo[3,2-c]quinoline (2o): Pale yellow solid (0.0896
g, 81%); m.p. 174-175 °C. IR (film) νmax 1637, 1570, 1306, 1264 cm-1.
1H NMR (300 MHz, CDCl3) δ: 7.42 (dd, J = 8.4, 4.8 Hz, 1H), 7.60-7.86
(m, 2H), 7.96 (dd, J = 8.4, 1.3 Hz, 1H), 8.17-8.43 (m, 2H), 8.71 (dd, J =
4.8, 1.2 Hz, 1H), 9.66 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 115.3,
116.9, 119.0, 120.6, 121.3, 127.3, 130.0, 130.2, 142.8, 144.4, 146.6,
148.2, 149.2, 159.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
2
MHz, CDCl3) δ: 112.2, 113.7 (d, 2J(C,F) = 19 Hz), 116.6 (d, J(C,F) = 19
Hz), 117.3, 118.9 (d, 3J(C,F) = 3 Hz), 120.9, 122.4, 124.3, 127.1 (d, 3J(C,F)
= 8 Hz), 127.7, 137.3 (d, 2J(C,F) = 12 Hz), 144.6, 156.0, 157.0 (d, 4J(C,F)
= 5 Hz), 158.6 (d, 1J(C,F) = 257 Hz) ppm. 19F NMR (282 MHz, CDCl3) δ:
-122 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. For C15H9FNO:
238.0668; found: 238.0661.
C14H9N2O: 221.0715; found: 221.0710.
6-Methylbenzofuro[3,2-c]quinoline (2p):[27] Pale yellow solid (0.029
g, 78%); m.p. = 132-134 °C (lit.[27] 132-133 °C). IR (film) νmax 3380,
1563, 1509, 1364, 1084 cm-1. 1H NMR (300 MHz, CDCl3) δ: 3.16 (s,
3H), 7.41-7.69 (m, 3H), 7.72-7.79 (m, 2H), 8.10 (dd, J = 7.6, 2.1 Hz,
2-Chlorobenzofuro[3,2-c]quinoline (2v):[53] White crystalline solid
(0.0865 g, 68%); m.p. 141-142 °C (lit.[53] 139-141 °C). 1H NMR (300
MHz, CDCl3) δ: 7.38-7.58 (m, 2H), 7.59-7.76 (m, 2H), 8.02 (dd, J = 7.6,
0.6 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 9.38 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 112.2 116.9, 117.7, 119.8,
120.7, 122.3, 124.2, 127.6, 130.0, 131.4, 132.9, 144.4, 145.5, 156.0,
156.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C15H9ClNO:
254.0373; found: 254.0368.
1H), 8.18 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 8.1, 2.1 Hz, 1H) ppm. 13
C
NMR (75 MHz, CDCl3) δ: 24.3, 112.1, 115.5, 116.2, 120.7, 121.8,
123.5, 124.0, 126.1, 126.7, 128.9, 129.4, 146.9, 154.8, 155.9, 157.5
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C16H12NO: 234.0919;
found: 234.0915.
2-Methoxybenzofuro[3,2-c]quinoline (2q):[27] Off-white solid (0.095
g, 84%); m.p. = 150-152 °C (lit.[27] 150-153 °C). IR (film) νmax 2954,
1350, 1514, 1468, 1228, 1191, 1031 cm-1. 1H NMR (300 MHz, CDCl3)
δ: 3.96 (s, 3H), 7.28-7.53 (m, 4H), 7.64 (d, J = 8.1 Hz, 1H), 7.97 (dd, J
= 7.4, 0.8 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 9.23 (s, 1H) ppm 13C NMR
(75 MHz, CDCl3) δ: 55.6, 98.5, 111.9, 116.4, 117.7, 120.6, 121.7,
122.8, 123.9, 127.1, 131.3, 141.5, 143.3, 155.8, 156.7, 158.2 ppm.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C16H12NO2: 250.0868; found:
250.0858.
6-Heptylbenzofuro[3,2-c]quinoline (2w): White solid (0.056 g, 70%);
m.p. = 90-92 °C. IR (film) νmax 2917, 1559, 1445, 1363, 1202 cm-1. 1H
NMR (300 MHz, CDCl3) δ: 0.88 (t, J = 6.7 Hz, 3H), 1.22-1.64 (m, 8H),
1.95 (dt, J = 15.7, 7.7 Hz, 2H), 3.40 (t, J = 8.0 Hz, 2H), 7.40-7.67 (m,
3H), 7.69-7.79 (m, 2H), 8.00 (d, J = 7.3 Hz, 1H), 8.19 (d, J = 8.4 Hz,
1H), 8.35 (d, J = 8.1 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 14.1,
22.7, 28.6, 29.2, 29.9, 31.8, 38.0, 112.1, 114.8, 116.2, 120.7, 121.8,
123.1, 124.0, 126.0, 126.6, 129.1, 129.3, 146.9, 155.9, 157.7, 159.0
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C22H24NO: 318.1858;
found: 318.1845.
3-Methoxybenzofuro[3,2-c]quinoline (2r): Off-white solid (0.091 g,
81%); m.p. = 146-147 °C. IR (film) νmax 3022, 1639, 1452, 1345, 1324,
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10.1002/ejoc.201800923
European Journal of Organic Chemistry
FULL PAPER
4.
5.
M. J. Mphahlele, L. G. Lesenyeho J. Heterocycl. Chem. 2013,
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Y. Nishihara Applied cross-coupling reactions, Vol. 80, Springer
Science & Business Media, 2012.
Synthesis of N-(2-bromophenyl)quinolin-4-amine (3): To
a
degassed solution of Pd2(dba)3 (2 mol%) and XantPhos (4 mol%) in
anhydrous 1,4-dioxane (4 mL/mmol) were added caesium carbonate
(1.4 equiv.), 4-bromoquinoline (1 equiv.) and 2-bromoaniline (1.1
equiv.) under a nitrogen atmosphere. The reaction mixture was stirred
at 120 °C under nitrogen for 24 h. The cooled reaction mixture was
diluted with DCM, filtered through Celite and concentrated in vacuo.
The crude mixture was purified by column chromatography over silica
gel using DCM/EtOAc (3:1) as eluent to yield the product as a yellow
solid (0.322 g, 74%); m.p. = 238-241 °C. IR (film) νmax 3360, 3061,
1572, 1526, 1335, 747 cm1. 1H NMR (300 MHz, CDCl3) δ: 6.88 (bs,
1H), 7.02 (td, J = 8.0, 1.5 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 7.31-7.38
(m, 1H), 7.51-7.61 (m, 2H), 7.65-7.78 (m, 2H), 8.01 (d, J = 8.3 Hz, 1H),
8.09 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H) ppm. 13C NMR (75
MHz, CDCl3) δ: 103.4, 116.9, 120.0, 120.3, 122.2, 125.0, 125.8, 128.4,
129.6, 130.1, 133.5, 138.3, 146.2, 149.2, 150.8 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C15H12BrN2: 299.0184; found: 299.0187.
6.
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J. Stille Angew. Chem. 1986, 98, 504-519.
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19.
Synthesis
of
11H-indolo[3,2-c]quinoline
(4)[54]
:
N-(2-
bromophenyl)quinolin-4-amine
3
(1 equiv.), Pd(OAc)2 (5 mol%),
PCy3.HBF4 (10 mol%) and caesium carbonate (2 equiv.) were added
to degassed N-methylpyrrolidone (1.5 mL/mmol) under Schlenk
conditions under a nitrogen atmosphere. The reaction mixture was
stirred at 150 °C (sand bath) for 3 h. The cooled reaction mixture was
diluted with DCM and filtered through Celite. The mixture was washed
with water (3 x 10 mL) and brine (15 mL), dried over MgSO4, filtered
and concentrated in vacuo. The crude mixture was purified by column
chromatography over silica gel using DCM/EtOAc (7:3) as eluent to
yield the product as an off-white solid (0.030 g, 83%); m.p. >250 °C
(lit.[54] 340-341 °C). IR (film) νmax 3355, 2916, 2849, 1567, 1512, 1459,
1236 cm-1. 1H NMR (300 MHz, DMSO-d6) δ: 7.35 (t, J = 7.5 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.63-7.81 (m, 3H), 8.15 (dd, J = 8.2, 1.3 Hz,
1H), 8.33 (d, J = 7.8 Hz, 1H), 8.53 (dd, J = 8.0, 1.4 Hz, 1H), 9.60 (s,
1H), 12.72 (s, 1H) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 112.3, 114.8,
117.6, 120.6, 121.1, 122.4, 122.6, 126.0, 126.1, 128.5, 130.0, 139.3,
140.2, 145.3, 145.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
M. K. Mehra, M. P. Tantak, I. Kumar, D. Kumar Synlett 2016, 27,
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The authors wish to thank the reviewers for the suggestion to try
the following reaction:
C15H11N2: 219.0922; found: 219.0911.
Supporting Information (see footnote on the first page of this article):
Additional competition experiments, as well as 1H, 13C and 19F NMR
spectra of all new compounds, key intermediates and final products.
mol
2
2
%
Pd(OAc)2
Cs2CO3
O
N
O
equiv.
Br
NMP, 135 °C, 18 h
N
78% Isolated Yield
Acknowledgements
31.
Substrates that failed to undergo clean coupling under the
optimised conditions:
O
Our research is supported by Science Foundation Ireland
(grant number SFI/12/IP/1315) and the Synthesis and Solid
State Pharmaceutical Centre (SSPC) (SFI/12/RC/2275). The
Authors thank the European Cooperation in Science and
Technology COST initiative for funding CA15106, C-H
Activation in Organic Synthesis (CHAOS). FJR, GMG, and
FOG acknowledge support from Enterprise Ireland (CF-2017-
0757-P).
N
H
O
S
O
N
Br
Br
Br
N
N
aldehydic
S-linker
p
-pyridinyl
32.
33.
34.
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When the Boc-protected substrate was subjected to the
optimized conditions, deprotected starting material (3) was
recovered exclusively.
J. P. Heiskanen, A. E. Tolkki, H. J. Lemmetyinen, O. E. O. Hormi
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Keywords: quinoline • direct arylation • CH activation •
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Under aerobic conditions the reaction proceeded sluggishly.
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Direct Arylation
Rachel M. Shanahan, Aobha Hickey, F.
Jerry Reen, Fergal O’Gara and Gerard
P. McGlacken *
Page No. – Page No.
A palladium-catalysed, phosphine-free, direct arylation of 4-phenoxyquinolines in air
is described. Using intramolecular direct arylation, the ring-closed products are
formed in isolated yields of up to 95%. This approach allows access to a range of
benzofuroquinolines, and an array of functional groups on both the quinoline and
phenoxy rings is tolerated.
Synthesis of benzofuroquinolines via
phosphine-free direct arylation of 4-
phenoxyquinolines in air .
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