Catalyst Control in Switching the Site Selectivity of C?H Olefinations of 1,2-Dihydroquinolines: An Approach to Positional-Selective Functionalization of Quinolines

Article abstract of DOI:10.1002/chem.201904512

A unique approach to achieve site-selective C?H olefinations exclusively at the C-3- or C-8-positions in the quinoline framework has been developed by catalyst control. Distal C(3)?H functionalization is achieved by using palladium catalysis, whereas proximal C(8)?H functionalization is obtained by employing ruthenium catalysis. Switching the site selectivity within a single substrate directly indicates two diverse pathways, which are operating under the palladium- and ruthenium-catalyzed reaction conditions.

Full text of DOI:10.1002/chem.201904512

A Journal of
Accepted Article
Title: Catalyst-control in Switching the Site-Selectivity of C−H
Olefinations of 1,2-dihydroquinolines: An Approach to Positional-
selective Functionalization of Quinolines.
Authors: Riki Das, Nandkishor Prakash Khot, Akanksha Santosh
Deshpande, and Manmohan Kapur
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To be cited as: Chem. Eur. J. 10.1002/chem.201904512
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Chemistry - A European Journal
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Catalyst-control in Switching the Site-Selectivity of C−H
Olefinations of 1,2-dihydroquinolines: An Approach to Positional-
selective Functionalization of Quinolines.
Riki Das,[a],[b]§ Nandkishor Prakash Khot,[a]§ Akanksha Santosh Deshpande and Manmohan Kapur*
[a]
[a]
Abstract:
A
unique approach to achieve site-selective C−H
organometallic reagents are mostly used in stoichiometric
amounts, thus often leading to unavoidable waste formation and
usually involving relatively thermodynamically-unstable
intermediates. In comparison, metal-hydrogen exchange via
transition metal complex-mediated C−H activation comes across
as a comparatively milder and a more functional group-tolerant
approach.7h
olefinations exclusively at the C-3 or C-8 positions in the quinoline
framework has been developed via catalyst-control. Distal C(3)−H
functionalization is achieved using palladium catalysis whereas,
proximal C(8)−H functionalization is obtained by employing ruthenium
catalysis. Switching site-selectivity within a single substrate directly
indicates two diverse pathways which are operating in the palladium
and ruthenium-catalyzed reaction conditions.
However, the late-stage, site-selective C−H functionalization on
the pre-existing quinoline scaffold is an equally challenging task
in the synthesis of complex molecules. A review of literature on
this topic reveals that a significant number of methods are well-
known for C-2 functionalization of quinoline using various
transition metal catalysts. Unlike pyridines,9 transition metal-
catalyzed functionalization of C-3 and C-4 position of quinolines
is not well-explored. A seminal work was reported by Kanai and
Introduction
8
Quinolines are one of the most familiar scaffolds, extensively
found in a wide range of natural products, drug molecules,
functional materials, and ligands in transition metal catalysis.1-4
Over the last few decades, a significant percentage of the
introduced drugs, where pharmacophores were heterocyclic
co-workers in which they achieved C-4 alkylated quinolines with
styrenes under cobalt-catalyzed conditions.10 Over the last few
decades, employment of N-oxides has been explored as a
directing group in transition metal catalyzed C-8 functionalization
of quinolines.11
5
compounds, were quinoline based. Even today, the development
of new and efficient methods for the synthesis of substituted
quinolines is amongst the primary tasks for organic chemists. In
this context, the pioneering and traditional methods for the
synthesis of substituted quinolines, such as the Combes
synthesis, Döbner-von Miller method, Friedlander quinoline
synthesis etc., at times suffer from some drawbacks such as
harsh reaction conditions, leading to limited substrate scope.6
Though one can consider that the substitution reaction on existing
simple quinoline motifs could be one of the valuable approaches
for the synthesis of functionalized quinolines, electrophilic
aromatic substitution is not suitable for electron-deficient
Results and Discussion
Based on our previous reports,12 we focused our efforts to toggle
the selectivity of C−H olefinations of 1,2-dihydro-N-acetyl
quinolines between C-3 and C-8 positions via catalyst-control. To
establish a switch in the selectivity governed by the electronic
nature of transition metal complexes, we use electrophilic
palladium (II)-complex, providing distal C(3)−H olefination,13
whereas cationic ruthenium complex leads to heteroatom-
directed, proximal C(8)−H olefination (Scheme 1).14
2
heteroarenes. Also, the sp -hybridized nitrogen atoms of aza-
heteroarenes frequently interact with electrophiles or Lewis acids,
thus leading to decrease of reactivity towards electrophiles. Direct
metal-hydrogen exchange or metal-halogen exchange with highly
basic organolithium or organomagnesium reagents, followed by
subsequent trapping with suitable electrophiles, causes
difficulties with functional group compatibility and unfavorable
7
nucleophilic aromatic substitution. Also, these main-group
[
a]
Dr. R. Das, N. P. Khot, A. S. Deshpande and Dr. M. Kapur
Department of Chemistry
Scheme 1. Catalyst-control in Site-selective C-H olefinations.
Indian Institution of Science Education and Research Bhopal
Bhopal Bypass Road, Bhauri, Bhopal 462066, MP, India
E-mail: mk@iiserb.ac.in
[
b]
Present address: Department of Chemistry, University of
Minnesota, Minneapolis, MN 55455-0431, USA
Our initial efforts started with the optimization of various catalyst
systems for C(3)−H and C(8)−H olefinations separately using 1,2-
dihydro-N-acetyl quinoline and methyl acrylate as the benchmark
substrates. Based on our previous experience with distal C−H
§
Equal Contribution
Supporting information for this article is given via a link at the end
of the document.
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functionalizations, we had anticipated that a significantly covalent
palladium catalyst could result in the functionalization at the C-3
position, whereas, a cationic catalyst would be necessary to give
the directed, proximal C-8 funationalization. Various palladium-
based catalyst systems were therefore screened with the
combination of suitable additive and oxidant for the optimization
of the electrophilic (non-directed) C(3)−H olefination (Table 1).
be [RuCl
mol%) as an additive, Cu(OAc)
oxidant as well as the base, in toluene as the solvent at 100 C
(Table 2, entry 3).
2
(p-cymene)]
2
(5 mol%) as the catalyst, AgSbF
6
(20
2
(2.0 equiv) acting as the terminal
o
Table 2. Attempts towards optimization of C(8)−H olefination of 1,2-dihydro-N-
acetyl quinolinesa
2
The reaction worked best with Pd(OAc) and did not provide
better transformations or yields with other Pd(II)-catalysts that
were screened. The transformation was optimized to complete
o
within 24 h at 80 C in presence of Pd(OAc)
2
(10 mol%) as the
Yield
%)
Entry
Reaction conditions
(
catalyst, Cu(OAc)
2
(1 equiv) and AgOAc (2 equiv) as the oxidant
1
[RuCl
Dioxane, 100 C, 24 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
t-AmOH, 100 C, 12 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
equiv), Toluene, 100 C, 20 h.
[RuCl (p-cymene)] (5 mol%), AgBF
Toluene, 100 C, 20 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
equiv), Toluene, 100 C, 24 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
Xylene, 120 C, 24 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
Toluene, 100 C, 24 h.
[RuCl (p-cymene)]
DMA, 100 C, 24 h.
2
(p-cymene)]
2
(5 mol%), AgSbF
6
(20 mol%), Cu(OAc)
2
2
(2.0 equiv),
(2.0 equiv),
21
NR
62
31
58
23
o
and base combination, in 1,4-dioxane as the solvent (Table 1,
entry 3).
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
2
2
6
(20 mol%), Cu(OAc)
o
2
2
6
(20 mol%), Cu(OAc)
(20 mol%), Cu(OAc) (2.0 equiv),
(20 mol%), Cu(OAc) .H O (2.0
(20 mol%), Cu(OAc)
(20 mol%), Cu(OTf)
2
(2.0
Table 1. Attempts towards optimization of C(3)−H olefination of 1,2-dihydro-N-
o
a
acetyl quinolines
2
2
4
2
o
2
2
6
2
2
o
2
2
6
2
(2.0 equiv),
(2.0 equiv),
(2.0 equiv),
(2.0 equiv),
(2.0 equiv),
(2.0 equiv),
(2.0 equiv),
o
a
2
2
6
2
NR
NR
NR
33
Yield
o
Entry
Reaction conditions
(
%)
2
2
(5 mol%), AgSbF
(5 mol%), AgSbF
(5 mol%), AgSbF
6
6
6
(20 mol%), Cu(OAc)
(20 mol%), Cu(OAc)
(20 mol%), Cu(OAc)
(20 mol%), Cu(OAc)
2
2
2
2
Pd(OAc)
2
o
(10 mol%), Cu(OAc)
THF, 65 C, 24 h.
2
(1.0 equiv), AgOAc (2.0 equiv),
o
1
4
[RuCl
DME, 80 C, 24 h.
[RuCl (p-cymene)]
DCE, 80 C, 24 h.
[RuCl (p-cymene)]
2
(p-cymene)]
2
2
2
Pd(OAc)
Toluene, 80 C, 24 h.
Pd(OAc) (10 mol%), Cu(OAc)
Dioxane, 80 C, 24 h.
Pd(OAc) (10 mol%), Cu(OAc)
equiv),Toluene,100 C, 24 h.
Pd(OAc) (10 mol%), Cu(OAc)
2
(10 mol%), Cu(OTf)
2
(1.0 equiv), AgOTf (2.0 equiv),
o
2
3
4
5
6
7
8
9
0
o
NR
56
5
1
1
1
1
1
1
1
1
2
2
2
(1.0 equiv), AgOAc (2.0 equiv),
o
o
2
(5 mol%), NaSbF
6
NR
2
2
(1.0 equiv), AgOAc (2.0
o
o
Toluene, 100 C, 24 h.
[RuCl (p-cymene)] (5 mol%), KSbF
Toluene, 100 C, 24 h.
[RuCl (p-cymene)] (5 mol%), AgSbF
Toluene, 100 C, 24 h.
[Cp*RhCl (3 mol%), AgSbF
Toluene, 100 C, 24 h.
DG = Boc, [RuCl (p-cymene)]
(2.0 equiv), Toluene, 100 C, 20 h
DG = Piv, [RuCl (p-cymene)] (5 mol%), AgSbF
(2.0 equiv), Toluene, 100 C, 20 h
DG = Ts, [RuCl (p-cymene)] (5 mol%), AgSbF
(2.0 equiv), Toluene, 100 C, 20 h
b
2
2
6
(20 mol%), Cu(OAc)
(20 mol%),
2
CM
NR
60
2
o
2
2
2
(1.0 equiv), AgOAc (2.0 equiv),
(1.0 equiv), AgOAc (2.0 equiv),
(1.0 equiv), AgOAc (2.0 equiv),
(1.0 equiv), AgOAc (2.0 equiv),
o
10
6
DCE, 80 C, 24 h.
2
2
6
O
2
(balloon),
Pd(OAc)
2
o(10 mol%), Cu(OAc)
o
DMA, 80 C, 24 h.
2
]
2
(15 mol%), Cu(OAc) (2.0 equiv),
6 2
Pd(OAc)
2
o(10 mol%), Cu(OAc)
o
CM
12
NR
20
DME, 80 C, 24 h.
2
2
(5 mol%), AgSbF
6
(20 mol%), Cu(OAc)
(20 mol%), Cu(OAc)
6
(20 mol%), Cu(OAc)
2
2
2
NR
CM
CM
Pd(OAc)
Dioxane, 80 C, 24 h.
PdCl (10 mol%), Ag
C, 12 h.
Pd(OAc) (10 mol%), Cu(OAc)
Dioxane, 80 C, 24 h.
2
(10 mol%), Cu(OTf)
2
o
o
2
2
6
2
2
O (1.5 equiv), AgOTf (0.5 equiv), Dioxane,
o
o
8
0
2
2
2
2
(1.0 equiv), Ag
2
O (2.0 equiv),
o
1
o
o
1
1
1
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
(10 mol%), Cu(OAc)
(10 mol%), AgOAc (2.0 equiv), Dioxane, 80 C, 24 h.
2
(1.0 equiv), Dioxane, 80 C, 24 h.
16
13
aOnly aromatization of starting material was observed; bC-3 olefinated product
was also observed; NR = no result; CM = Complex mixture.
o
(5 mol%), Cu(OAc) (1.0 equiv), AgOAc (2.0 equiv),
2
1
1
1
1
3
4
5
6
o
41
17
32
45
Dioxane, 80 C, 30 h.
Pd(OAc) (2.5 mol%), Cu(OAc)
Dioxane, 80 C, 30 h.
Pd(OAc) (10 mol%), Cu(OAc)
4 h.
PdCl
equiv), Dioxane, 80 C, 24 h.
PdCl (10 mol%), Cu(OAc)
Dioxane, 80 C, 24 h.
Pd(tfa) (10 mol%), Cu(OAc)
Dioxane, 80 C, 24 h.
DG = Boc, Pd(OAc) o(10 mol%), Cu(OAc)
equiv), Dioxane, 80 C, 24 h.
DG = Piv, Pd(OAc) o(10 mol%), Cu(OAc)
equiv), Dioxane, 80 C, 24 h.
DG = Ts, Pd(OAc) (o10 mol%), Cu(OAc)
equiv), Dioxane, 80 C, 24 h.
Table 3. Substrate scope of C(3)−H olefinations of 1,2-dihydro-N-acetyl
2
2
(1.0 equiv), AgOAc (2.0 equiv),
o
quinolines.
o
2
2
(1.0 equiv), O
2
, Dioxane, 80 C,
2
2
(MeCN)
2
2
(10 omol%), Cu(OAc) (1.0 equiv), AgOAc (2.0
2
2
(1.0 equiv), AgOAc (2.0 equiv),
2
(1.0 equiv), AgOAc (2.0 equiv),
1
1
7
8
o
42
39
2
o
1
2
2
9
0
1
2
2
(1.0 equiv), AgOAc (2.0
CM
CM
CM
2
2
(1.0 equiv), AgOAc (2.0
2
2
(1.0 equiv), AgOAc (2.0
NR = no result; CM = Complex mixture
Decent yields and exclusive regioselectivity was obtained in this
palladium catalyzed C(3)−H olefination reaction. Excluding either
AgOAc or Cu(OAc)
2
from the reaction was detrimental to the
transformation. Use of other terminal oxidants, including O
2
, did
not improve the transformation and the reaction did not work at all
without the palladium catalyst. The optimization of heteroatom-
directed C(8)−H olefination was initiated with the use of various
ruthenium-based catalyst systems. Combination of [RuCl
2
(p-
cymene)] and AgSbF i.e. cationic ruthenium complex was found
to be more effective for this transformation (Table 2). After
extensive optimization, the best reaction conditions were found to
2
6
aYield for the reaction carried out on 1 mmol scale.
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The reaction did not perform well without the Ag-additive and the
functional groups were well-tolerated, thereby increasing the
synthetic utility of the method over the traditional Heck reaction.
To check the reversibility of C−H bond cleavage step, both, the
palladium-catalyzed as well as ruthenium-catalyzed reactions
Cu(OAc)
base. The reaction did not work with O
Table 2, entry 13). Toluene was found to be the best solvent for
2
was necessary as the terminal oxidant as well as the
2
as the terminal oxidant
(
the transformation and in absence of the ruthenium catalyst, the
reaction did not work at all. Despite the cationic rhodium catalyst
system also working almost equally well (Table 2, entry 14), we
preferred to use the ruthenium catalyst since it was relatively less
expensive. With the optimal reaction conditions in hand, the scope
of C(3)−H olefination of 1,2-dihydro-N-acetyl quinoline was
explored as shown in Table 3. The site-selectivity was exclusive
as expected. Halogen functional groups on the quinoline
framework as well as the olefin coupling partner were also
compatible under this reaction condition. In some cases, the
reactions did not proceed beyond a certain point and the starting
material was recovered back. Electron-withdrawing substituents
2
were carried out in presence of D O and MeOH-d4 (Scheme 2).
No D-incorporation was observed in recovered starting materials
under the palladium-catalyzed C−H metallation conditions thus
indicating it to be an irreversible electrophilic metallation. Under
the ruthenium-catalyzed heteroatom-directed C−H metallation
2
conditions, 7% D-incorporation was observed in presence of D O
and about 5% D-incorporation was observed in presence of
MeOH-d4, thus indicating a reversible C−H metallation step. The
studies for determining whether the C−H cleavage step was
kinetically relevant, were performed for both the C-3 and C-8
olefinations separately (Scheme 3).16 The observed kinetic
isotope effect values for the palladium-catalyzed transformation
were close to 1.0, which suggests that in that case the C-H bond
cleavage is not the rate-limiting step. The ruthenium-catalyzed
transformation showed a mild kinetic isotope effect and therefore
rate studies with respect to the starting material and the two
catalysts were carried out, but they were not very conclusive.16
such as −NO
2
led to decreased electron-density on the
dihydroquinoline and were not compatible under this reaction
condition (Table 3, 3i). Notably, the reaction did not work with
electron-neutral olefins (Table 3, 3n-o).
Simultaneously, the scope of C(8)−H olefination of 1,2-dihydro-N-
acetyl quinolines was explored under its optimized reaction
condition. This protocol was compatible with a wide range of
functional groups, such as electron-donating as well as electron-
withdrawing substituents on the phenyl ring of both the coupling
partners (Table 4). Unlike C−3 olefination, the electron-
withdrawing nitro-substituent worked well in this reaction
condition (Table 4, 4f). The site-selectivity was exclusive as
expected.
Table 4. Substrate scope of C(8)−H olefinations of 1,2-dihydro-N-acetyl
quinolines.
Scheme 2. Studies to check reversibility of metallation.
Control experiments were performed to check whether blocking
the preferred site for metallation would lead to a switch in
selectivity for that metal (Scheme 4). These studies confirmed that
for this substrate, the preferences were exclusive and the site-
selectivity for each of transition metal employed was limited to the
specific position. This further indicates that the modes of C−H
functionalization for the C(3)−H and the C(8)−H are quite different.
On the basis of the control experiments and mechanistic studies,
the plausible mechanisms for C-3 and C-8 olefinations are
proposed in Scheme 5.
aYield for the reaction carried out on 1 mmol scale.
As observed for the palladium catalysis, under the ruthenium
catalysis condition too, the reaction did not work with
electronically-unbiased olefins (Table 4, 4q−r). Other directing
groups (Boc, Pivaloyl, Tosyl) failed to give the olefinated product
Scheme 3. Experiments to determine kinetic isotope effect.
(
Table 4, 4v−x). In both the transformations, the palladium-
catalyzed, as well as the ruthenium-catalyzed one, halogen
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Based on our previous reports as well as others,12-14 palladium-
catalyzed C−H activation in such heterocycles could proceed via
an electrophilic palladation, which is followed by olefin insertion to
give the intermediate 12. Subsequent β-hydride elimination leads
to the desired C-3 olefinated products (Scheme 5).
Scheme 4. Control reactions.
On the other hand, the ruthenium-catalyzed heteroatom-directed
C(8)−H olefination is expected to initiate with the generation of the
cationic ruthenium complex. Coordination of the metal to the
Lewis-basic carbonyl oxygen followed by the acetate assisted
C−H activation leads to the ruthenacycle 13. This is followed by
the coordination of the olefin, subsequent migratory insertion and
β-hydride elimination leads to the desired product (Scheme 5).
The intermediate 15 arising out of carboruthenation was detected
in ESI-HRMS.
To highlight the synthetic potential of these protocols, the key
question centered on the ability to remove the directing group or
activating tether from the product. Therefore, the removal of acetyl
group was necessary to get diversely functionalized quinolines
and demonstrate the utility of the current method. A series of C-3
and C-8 olefinated 1,2-dihydro-N-acetyl quinolines were refluxed
in dioxane in presence of DDQ which led to a library of C-3 and
C-8 olefinated quinolines in good to excellent yields (Scheme 6).
The substrates bearing halogen functional groups (17d, 17j,
Scheme 6) also performed very well in these transformations.
Scheme 5. Plausible mechanisms for the Pd-catalyzed as well as the Ru-
catalyzed C-H functionalizations.
Conclusions
In conclusion, a clear distinction has been demonstrated between
the two modes of C−H olefinations such as palladium-catalyzed
distal C−H functionalization and ruthenium-catalyzed proximal
C−H activation. Switching site-selectivity makes it possible to
access an array of structurally diverse C-3 as well as C-8
olefinated quinolines from a single starting material. Well-
tolerated halogen-substitutions on quinolines add further
advantage to these methods. The development of this novel
methodology to bring about C−H activation at two different sites
within a single substrate by choosing the appropriate transition
metal complex is expected to have good implications for newer
approaches for the synthesis of substituted quinolines.
Scheme 6. Removal of activating tether and aromatization.
Experimental Section
(i) General Methods:
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All commercially available compounds were used without purification.
Unless otherwise noted, all reactions were performed in oven-dried
glassware. All reactions were run under argon or nitrogen atmosphere. All
solvents used in the reactions were purified before use. Tetrahydrofuran
as well as toluene were distilled from sodium and benzophenone, whereas
dry dichloromethane, dimethylformamide, and dichloroethane were
Prepared according to the general procedure (A) on 500 mg scale and the
title compound was isolated as a pale-yellow gel (36% yield, 230 mg). H
NMR (400 MHz, CDCl ) δ 7.05 (d, J = 7.1 Hz, 1H), 6.77 (dd, J = 8.6, 2.6
3
Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 9.5 Hz, 1H), 6.22 – 6.10 (m,
1H), 4.48 (s, 2H), 3.84 (s, 3H), 2.18 (s, 3H). Spectral data obtained were
in good agreement with those reported in the literature.17
1
2
distilled from CaH . Petroleum ether with a boiling range of 40–60 °C was
used. Melting points are uncorrected. 1H, and 13C NMR: Recorded on
Bruker Avance III 400 MHz NMR Spectrometer, Bruker Avance III 500
1-(6-methylquinolin-1(2H)-yl)ethan-1-one (1e):
MHz NMR Spectrometer; spectra were recorded at 295 K in CDCl
chemical shifts are calibrated to the residual proton and carbon resonance
of the solvent: CDCl
(1H δ 7.25; 13C δ 77.0). HRMS: Bruker Daltonics
MicroTOF-Q-II with electron spray ionization (ESI) or Atmospheric
pressure chemical ionization (APCI). GC-HRMS: Performed on Agilent
3
;
Prepared according to the general procedure (A) on 500 mg scale and the
title compound was isolated as a pale-yellow gel (52% yield, 340 mg). H
1
3
NMR (400 MHz, CDCl
3
): δ 6.95-6.83 (m, 3H), 6.38 (d, J = 9.6 Hz, 1H),
5
.99-5.95 (m, 1H), 4.35 (s, 2H), 2.23 (s, 3H), 2.09 (s, 3H). Spectral data
12a
obtained were in good agreement with those reported in the literature.
-(6-bromoquinolin-1(2H)-yl)ethan-1-one (1f):
Prepared according to the general procedure (A) in 100 mg scale and the
7
200 GC-QToF (with Electron Impact (EI), 70eV) with 7890A GC using
DB-5 column. GC-LRMS: Performed on Agilent 7890A GC with Agilent
975C MS (EI 70 eV) using DB-5 column. IR: Perkin Elmer Spectrum BX
1
5
FTIR, Shimadzu IRAffinity-1 FTIR and were recorded as thin films between
KBr plates. Kinetic studies were performed on Agilent Infinity 1290 Series
HPLC using Agilent Zorbax-NH2 (4.6 x 250 mm, 5 micron) analytical
column.
title compound was isolated as a yellow gel (63% yield, 78 mg). TLC R
f
1
0.30 (3:2, Petroleum ether:EtOAc); H NMR (500 MHz, CDCl
3
): δ 7.32 (dd,
J = 8.5, 2.3 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.08 (bs, 1H), 6.46 (dt, J =
9
.6, 1.6 Hz, 1H), 6.14 (dd, J = 8.8, 4.2 Hz, 1H), 4.44 (s, 2H), 2.20 (s, 3H);
(
ii) General Procedures and analytical data:
1
3C NMR (101 MHz, CDCl
3
): δ 169.9, 135.2, 133.0, 131.8, 131.2, 129.8,
-
1
129.1, 125.3, 121.9, 50.2, 22.5; IR (KBr, cm ): 3398, 2904, 1636, 1444,
11BrNO [M+H]+ 252.0019 and
1267, 1153, 1012, 905; ESI-HRMS: C11
253.9998, found 252.0022 and 254.0032.
(A) General procedure for the synthesis of 1-(quinolin-1(2H)-yl)
H
ethan-1-one (1a):
Sodium borohydride (5.86 g, 155.5 mmol) was added portion-wise to a
1
-(6-chloroquinolin-1(2H)-yl)ethan-1-one (1g):
stirring mixture of quinoline (5 g, 38.75 mmol), acetic anhydride (20 mL,
o
2
05.05 mmol) and acetic acid (60 mL), over a period of 1.5 h at 0 C. After
the addition was complete, the mixture was warmed to 50 oC for 30 min.
The reaction mixture was concentrated under vacuum, diluted with water
Prepared according to the general procedure (A) on 500 mg scale and the
title compound was isolated as a pale-yellow gel (41 % yield, 267 mg). H
NMR (400 MHz, CDCl
Hz, 1H), 6.47 (dt, J = 9.5, 1.5 Hz, 1H), 6.24 – 6.08 (m, 1H), 4.44 (s, 2H),
1
3
) δ 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.10 (d, J = 1.9
(
500 mL) and neutralized with sodium hydrogen carbonate. This mixture
was then extracted with EtOAc and the organic extract was dried over
anhydrous Na SO and concentrated under reduced pressure. The
resulting crude oil was purified by silica gel column chromatography (71%).
1H NMR (400 MHz, CDCl
): δ 7.12-6.99 (m, 4H), 6.42 (d, J = 9.6 Hz, 1H),
.99-5.95 (m, 1H), 4.34 (s, 2H), 2.09 (s, 3H). Spectral data obtained were
in good agreement with those reported in the literature.12a
2.20 (s, 3H). Spectral data obtained were in good agreement with those
2
4
17
reported in the literature.
3
1-(5-bromoquinolin-1(2H)-yl)ethan-1-one (1h):
5
Prepared according to the general procedure (A) in 100 mg scale and the
title compound was isolated as a yellow gel (52% yield, 63 mg). TLC R
1
-(8-methylquinolin-1(2H)-yl)ethanone (1b):
f
1
1
0
(
(
.30 (3:2, Petroleum ether:EtOAc); H NMR (500 MHz, CDCl
500 MHz, CDCl ): δ 7.44 (d, J = 9.1 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.92
dt, J = 9.7, 1.7 Hz, 1H), 4.45 (s, 2H), 2.22 (s, 3H); 13C NMR (101 MHz,
): δ 170.0, 138.5, 129.7, 128.8, 127.7, 125.5, 123.3, 121.5, 53.4,
3
): δ H NMR
3
Prepared according to the general procedure (A) on 100 mg scale and the
title compound was isolated as a colorless gel (71% yield, 93 mg). TLC R
f
1
CDCl
3
0
7
6
2
1
5
3
.30 (3:2, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl ): δ 7.17 –
-
1
22.4; IR (KBr, cm ): 3410, 2788, 1626, 1465, 1346, 1232, 1051, 8798;
.09 (m, 2H), 7.00 – 6.94 (m, 1H), 6.52 (dd, J = 9.4, 2.2 Hz, 1H), 6.20 –
.13 (m, 1H), 5.41 (dd, J = 16.7, 5.7 Hz, 1H), 3.43 (d, J = 16.7 Hz, 1H),
ESI-HRMS: C12
and 254.0032.
H
14NO [M+H]+ 252.0019 and 253.9998, found 252.0022
.28 (s, 3H), 1.88 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 164.5, 151.6,
48.7, 121.6 (2C), 120.4, 110.7 (2C), 110.4, 67.6, 56.0 (d, J = 3.55, 1C),
3
-
1
1-(3-bromoquinolin-1(2H)-yl)ethan-1-one (1i):
4.9; IR (KBr, cm ): 3368, 2900, 1645, 1439, 1392, 1208, 1124, 886, 761;
+
ESI-HRMS: C12
H
14NO [M+H] 188.1070, found 188.1051.
Prepared according to the general procedure (A) in 500 mg scale and the
title compound was isolated as a colorless gel (78% yield, 475 mg). TLC
1-(3-methylquinolin-1(2H)-yl)ethanone (1c):
1
R
f
0.30 (3:2, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
): δ 7.31
–
7.14 (m, 3H), 7.11 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 4.70 (s, 2H), 2.23 (s,
H); 13C NMR (100 MHz, CDCl
): δ 170.0, 135.2, 129.1, 127.6, 126.0,
26.0 (2C), 124.1, 48.4, 22.4; IR (KBr, cm ): 3400, 2956, 1668, 1441,
320, 1217, 1098, 906, 759, 601; ESI-HRMS: C11
NO [M+H]+
Prepared according to the general procedure (A) in 100 mg scale and the
3
1
1
3
title compound was isolated as a yellow gel (67% yield, 87 mg). TLC R
f
-
1
1
0
6
3
1
1
1
.30 (3:2, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
): δ 7.19 –
11 r
H B
.99 (m, 4H), 6.25 (d, J = 1.2 Hz, 1H), 4.33 (s, 2H), 2.20 (s, 3H), 1.92 (s,
H); 13C NMR (100 MHz, CDCl
252.0019 and 253.9998, found 251.9990 and 253.9977.
3
): δ 170.2, 138.7, 135.6, 130.2, 128.6,
-
1
26.1, 125.7, 123.5, 121.1, 45.7, 22.5, 20.9; IR (KBr, cm ): 3412, 2858,
632, 1451, 1380, 1221, 1116, 1006, 804; ESI-HRMS: C12
88.1070, found 188.1070.
H
14NO [M+H]+
(B) Synthesis of 1-(6-nitroquinolin-1(2H)-yl)ethan-1-one (1j):
To an ice-cold solution of 6-nitroquinoline (0.5 g, 2.85 mmol) in acetic acid
(3 mL) was added sodium borohydride (0.108 g, 2.85 mmol) in small
1-[6-methoxyquinolin-1(2H)-yl]ethan-1-one (1d):
portions (the reaction was monitored by TLC). Upon completion of the
reaction, the mixture was carefully poured onto crushed ice and stirred
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Chemistry - A European Journal
10.1002/chem.201904512
FULL PAPER
vigorously and then filtered. The reddish-brown solid that was obtained,
was dried well and used as such without purification for the next step
(E) Synthesis of 1-tosyl-1, 2-dihydroquinoline (1n):
(
crude yield 70 %).
A solution of quinoline (500 mg, 3.87 mmol) in dry THF (4 mL) was added
slowly to an ice-cold suspension of lithium aluminum hydride (172 mg, 4.64
mmol) in dry THF (10 mL). The solution was stirred for 2 h at 0 C, during
which the conversion was complete. The reaction was then carefully
quenched by ice and filtered. The filtrate was extracted with EtOAc,
o
To an ice-cold solution of 6-nitro-1, 2-dihydroquinoline (0.45 g, 2.56 mmol),
pyridine (1.3 mL, 15.56 mmol) in DCM (8 mL) was added acetyl chloride
(0.6 mL, 7.66 mmol), dropwise, and the resulting mixture was stirred for an
hour at the same temperature before being warmed to RT and stirred for
another 16 h during which the reaction was found to be complete. Upon
dilution with EtOAc, the mixture was washed with water and brine, dried
washed successively with brine, dried over anhyd. Na
2
SO
4
and
concentrated under reduced pressure. The resulting colorless solid was
used immediately without purification for next step (crude yield 406 mg,
80 %).
2 4
over anhydrous Na SO and concentrated under reduced pressure. The
crude product was purified by silica gel flash column chromatography
1
(
(
6
81%). H NMR (400 MHz, CDCl
3
): δ 8.06 (dd, J = 8.8, 2.4 Hz, 1H), 7.95
A solution of 1, 2-dihydoquinoline (300 mg, 2.29 mmol) and DMAP (14 mg,
0
addition of triethylamine (0.94 mL, 6.67 mmol) to this stirring solution, the
resulting reaction mixture was stirred for another 20 min. A solution of TsCl
d, J =2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 6.22-
.17 (m, 1H), 4.46 (dd, J = 3.6, 1.2 Hz, 2H), 2.26 (s, 3H). Spectral data
obtained were in good agreement with those reported in the literature.12a
.11 mmol) in dry DCM (5 mL) was cooled to 0 oC. After a dropwise
(
512 mg, 2.74 mmol) in DCM (2 mL) was then added dropwise to this
1-(2-methylquinolin-1(2H)-yl)ethan-1-one (1k):
reaction mixture and the resulting solution was stirred for another 14 h at
0 oC. This reaction mixture was diluted with EtOAc, washed successively
2 4
with brine, dried over anhyd. Na SO and concentrated under reduced
pressure. The crude product was purified by silica gel column
Prepared according to the general procedure of (B) on 500 mg scale and
the title compound was isolated as a greenish-gel (57% yield, 373 mg). H
1
chromatography (eluent: Petroleum ether:EtOAc, 4:1) to give 1n as a
NMR (400 MHz, CDCl
3
) δ 7.26 – 7.03 (m, 4H), 6.47 (d, J = 9.3 Hz, 1H),
1
colorless solid. Yield: 514 mg, (80%). H NMR (400 MHz, CDCl
3
): δ 7.68
6.12 (dd, J = 9.3, 5.9 Hz, 1H), 5.49 (bs, 1H), 2.25 (s, 3H), 1.09 (d, J = 6.6
(d, J = 7.6 Hz, 1H), 7.28 − 7.22 (m, 3H), 7.15 (t, J = 7.6 Hz,1H), 7.05 (d, J
Hz, 3H). Spectral data obtained were in good agreement with those
reported in the literature.18
= 8.4 Hz, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.00 (d, J = 9.6 Hz, 1H), 5.58 − 5.53
(
m, 1H), 4.41 (dd, J = 2.8,1.2 Hz, 2H), 2.31 (s, 3H). Spectral data obtained
12a
were in good agreement with those reported in the literature.
(C) Synthesis of tert-butyl quinoline-1(2H)-carboxylate (1l):
(
F) General procedure for the synthesis of 3-alkenyl-1,2-dihydro-N-
A solution of 1,2-dihydroquinoline (300 mg, 2.29 mmol) and DMAP (3 mg,
o
acetyl-quinolines:
0
.23 mmol) in dry DCM (15 mL) was cooled to 0 C. Triethylamine (1 mL,
.87 mmol) was added dropwise and the resulting reaction mixture was
6
stirred for 20 min at 0 oC. This was followed by the slow addition of a
In a pressure tube equipped with a stir bar, N-acetyl-1,2-dihydroquinoline
0.300 mmol) was dissolved in dry dioxane (1.5 mL). The reaction mixture
was degassed for 10 min followed by the addition of Pd(OAc) (0.030
mmol), Cu(OAc) (0.300 mmol), AgOAc (0.600 mmol), and the olefin
(
solution of di-tert-butyl dicarbonate (0.81 mL, 3.44 mmol) in DCM (5 mL).
The reaction mixture was stirred for 14 h at 0 oC, during which the
conversion was complete. Upon dilution with DCM, mixture was washed
successively with brine and water. The combined organic extract was dried
2
2
coupling partner (0.600 mmol). The tube was fitted with Teflon screw cap
under an argon flow. The reaction mixture was heated to 80 C and allowed
o
2 4
over anhyd. Na SO and concentrated under reduced pressure. The crude
to stir for 15-30 h (total time), during which the reaction was found to be
complete (as indicated by TLC). Upon cooling to room temperature, the
reaction mixture was diluted with EtOAc and filtered through a pad of Celite.
The filtrate was concentrated under reduced pressure and the crude
product was purified by silica gel flash column chromatography.
product was purified by silica gel column chromatography (eluent:
Petroleum ether:EtOAc, 4:1) and isolated as a yellow gel (354 mg (61%)).
1H NMR (400 MHz, CDCl
3
): δ 7.55 (d, J = 8 Hz, 1H), 7.21 − 7.11 (m, 1H),
7.08 − 6.99 (m, 2H), 6.46 (d, J = 8 Hz, 1H), 6.00 − 5.95 (m, 1H), 4.35 (dd,
J = 2.4, 1.8, 1H), 1.51 (s, 9H). Spectral data obtained for 1l were in good
agreement with those reported in the literature.12a
Methyl (E)-3-(1-acetyl-1,2-dihydroquinolin-3-yl)acrylate (3a):
(D) Synthesis of 2,2-dimethyl-1-(2-methylquinolin-1(2H)-yl)propan-1-
one (1m):
Reaction time 15 h, Yield: 56% (41 mg), Physical appearance: Pale yellow
1
gel, TLC R
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
):
δ 7.43 (d, J = 16.0 Hz, 1H), 7.34–7.17 (m, 4H), 6.82 (s, 1H), 6.13 (d, J =
6.0 Hz, 1H), 4.65 (s, 2H), 3.81 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz,
CDCl ): δ 170.0, 167.3, 142.2, 137.4, 131.9, 128.8, 128.6, 127.8, 125.9,
123.7, 118.2, 51.8, 49.2, 22.5; IR (KBr, cm ): 3464, 2925, 2855, 1737,
1458, 1376, 1169, 989, 889, 760; ESI-HRMS: C15
Na [M+Na]+
80.0944, found 280.0966.
A solution of methyl lithium (1.5 equiv.) was added dropwise to the solution
of quinoline (300 mg, 2.33 mmol) in THF (6 mL) under an argon
1
o
3
atmosphere, at -78 C. The temperature was gradually allowed to increase
-
1
o
to 25 C over 30 minutes and then maintained for another hour, following
o
H15NO
3
which the reaction mixture was cooled to 0 C and pivaloyl chloride (0.42
2
mL, 3.44 mmol) was added dropwise. The solution was stirred for a further
3
0 minutes at RT and then diluted with a saturated solution of NH
mixture was extracted with ethyl acetate and washed successively with
brine. The organic layer was dried over Na SO , filtered and concentrated
4
Cl. This
Ethyl (E)-3-(1-acetyl-1,2-dihydroquinolin-3-yl)acrylate (3b):
2
4
under reduced pressure. The resulting yellow oil was purified by silica gel
column chromatography (eluent: Petroleum ether:EtOAc, 4:1). Yield: 72%
Reaction time 15 h, Yield: 53% (41 mg), Physical appearance: Pale-yellow
1
gel, TLC R
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
):
(
383 mg), Physical appearance: Yellow gel, TLC R
f
0.20 (4:1, Petroleum
δ 7.42 (d, J = 15.8 Hz, 1H), 7.33 – 7.17 (m, 4H), 6.81 (s, 1H), 6.13 (d, J =
1
ether:EtOAc); H NMR (400 MHz, CDCl
3
): δ 7.40 (d, J = 8.3 Hz, 1H), 7.24
1
=
1
1
5.8 Hz, 1H), 4.65 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl
): δ 170.0, 166.9, 141.9, 137.4,
−
9
3
1
1
7.18 (m, 1H), 7.15 – 7.09 (m, 2H), 6.51 (d, J = 9.4 Hz, 1H), 6.14 (dd, J =
3
.4, 5.9 Hz, 1H), 4.97 (p, J = 6.5 Hz, 1H), 1.34 (s, 9H), 1.11 (d, J = 6.7 Hz,
31.7, 130.1, 128.9, 128.5, 127.8, 125.9, 123.7, 118.7, 60.6, 41.2, 22.5,
H).; 13C NMR (100 MHz, CDCl
): δ 178.7, 135.3, 131.6, 128.3, 126.91,
3
-1
4.3; IR (KBr, cm ): 3400, 2981, 1710, 1376, 1265, 1180, 1034, 759; ESI-
-
1
26.85, 125.9, 125.2, 125.1, 49.5, 40.5, 29.4, 17.6; IR (KBr, cm ): 2861,
+
HRMS: C16
H17NO
3
Na [M+Na] 294.1101, found 294.1083.
+
657, 1452, 1032, 856, 745; ESI-HRMS: C15
H
19NONa [M+Na] 252.1364,
found 252.1368.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201904512
FULL PAPER
(
(
E)-methyl
3-(1-acetyl-8-methyl-1,2-dihydroquinolin-3-yl)acrylate
NMR (400 MHz, CDCl
6.69 (s, 1H), 6.09 (d, J = 15.9 Hz, 1H), 4.57 (s, 2H), 4.21 (q, J = 7.1 Hz,
3
): δ 7.35 (d, J = 15.9 Hz, 1H), 7.22 – 7.15 (m, 3H),
3c):
2
1
H), 2.19 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CD
69.7, 166.6, 141.4 (2C), 135.8, 131.2, 130.3(2C), 128.2, 127.3, 124.9,
3 3
Cl ): δ
Reaction time 15 h,Yield: 56% (40 mg), Physical appearance: Colorless
-
1
o
1
119.7, 60.7, 41.2, 22.5, 14.3; IR (KBr, cm ): 3378, 2987, 2769, 2459, 1856,
solid, M. p. 98-100 C, TLC R
400 MHz, CDCl ): δ 7.39 (d, J = 15.9 Hz, 1H), 7.23 − 7.11 (m, 2H), 7.10
7.05 (m, 1H), 6.77 (s, 1H), 6.14 (d, J = 15.9 Hz, 1H), 5.68 (d, J = 15.9
Hz, 1H), 3.77 (s, 3H), 3.50 (d, J = 15.9 Hz, 1H), 2.31 (s, 3H), 1.88 (s, 3H);
13C NMR (100 MHz, CDCl
): δ 171.6, 167.4, 142.3, 137.6, 137.0, 132.8,
32.2, 131.4, 130.5, 126.6, 125.4, 118.2, 51.8, 41.7, 21.2, 18.1; IR (KBr,
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR
+
1075, 989; ESI-HRMS: C16
H
17ClNO
3
[M+H] 306.0891, found 306.0873.
(
3
−
4-Chlorobenzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-3-yl)acrylate (3j):
3
1
Reaction time 30 h, Yield: 64% (67 mg), Physical appearance: Pale-yellow
-
1
cm ): 3423, 2876, 1734, 1347, 1260, 1206, 989, 811; ESI-HRMS:
0.20 (4:1, Petroleum ether:EtOAc); 1H NMR (400 MHz,
gel, TLC R
CDCl ):δ 7.45 (d, J = 15.8 Hz, 1H), 7.40–7.18 (m, 8H), 6.82 (s, 1H), 6.17
d, J = 15.8 Hz, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 2.24 (s, 3H); 13C NMR (100
MHz, CDCl ): δ 170.0, 166.5, 142.7, 137.5, 134.5, 134.2, 132.2, 129.6,
128.8, 128.7, 127.9, 125.9, 123.7, 118.0, 65.6, 41.3, 22.5; IR (KBr, cm ):
f
+
C
16
H
18NO
3
[M+H] 272.1281, found 272.1266.
3
(
Methyl
3d):
(E)-3-(1-acetyl-2-methyl-1,2-dihydroquinolin-3-yl)acrylate
3
-
1
(
3
434, 3409, 2924, 1714, 1651, 1494, 1373, 1261, 1165, 1093, 1014, 809,
+
757; ESI-HRMS: C21
3
H18ClNO Na [M+Na] 390.0867, found 390.0888.
Reaction time 15 h, Yield: 70% (51 mg), Physical appearance: Yellow gel,
TLC R ): δ
0.20 (4:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl
.36 (d, J = 15.8 Hz, 1H), 7.32–7.17 (m, 4H), 6.72 (s, 1H), 6.14 (d, J = 15.8
Hz, 1H), 5.82 (bs, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CD
Cl ): δ 169.6, 167.4, 142.3, 140.0, 135.4, 130.3,
28.7, 128.0, 127.7, 125.7, 124.7, 118.0, 53.5, 51.7, 22.8, 16.8; IR (KBr,
f
3
7
4-Nitrobenzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-3-yl)acrylate (3k):
3
3
Reaction time 30 h,Yield: 61% (66 mg), Physical appearance: Pale-yellow
1
solid, M. p. 117-119 oC, TLC R
0.30 (7:3, Petroleum ether:EtOAc); 1
f
H
-
1
cm ): 3447, 2980, 1714, 1667, 1487, 1368, 1326, 1269, 1169, 982, 848,
NMR (400 MHz, CDCl
2
=
3
): δ 8.24 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz,
H), 7.48 (d, J = 15.8 Hz, 1H), 7.34–7.18 (m, 4H), 6.84 (s, 1H), 6.19 (d, J
15.8 Hz, 1H), 5.33 (s, 2H), 4.65 (s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz,
): δ 170.0, 166.3, 147.7, 143.4, 143.3, 137.5, 135.1, 132.6, 128.8,
128.7, 128.3, 128.0, 125.9, 123.8, 123.7, 117.4, 64.8, 41.1, 22.5; IR (KBr,
+
7
60, 618; ESI-HRMS: C16
H
17NO
3
Na [M+Na] 294.1101, found 294.1082.
Benzyl
3e):
(E)-3-(1-acetyl-2-methyl-1,2-dihydroquinolin-3-yl)acrylate
CDCl
3
(
-
1
cm ): 3434, 3064, 1713, 1643, 1520, 1487, 1348, 1156, 982, 846, 737,
+
604, 527; ESI-HRMS: C21
H N O
19 2 5
[M+H] 379.1288, found 379.1300.
Reaction time 30 h, Yield: 62% (57 mg), Physical appearance: Yellow gel,
TLC R ): δ
0.30 (4:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl
.46–7.16 (m, 10H), 6.74 (s, 1H), 6.21 (d, J = 15.8 Hz, 1H), 5.83 (s, 1H),
.34 – 5.19 (m, 2H), 2.25 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H); 13C NMR (101
): δ 169.6, 166.7, 142.6, 140.0, 136.0, 135.4, 130.5, 128.7,
28.6, 128.28, 128.27, 127.8, 125.7, 124.7, 118.1, 66.4, 46.1, 22.9, 16.8;
f
3
7
5
4-Methoxybenzyl
(3l):
(E)-3-(1-acetyl-1,2-dihydroquinolin-3-yl)acrylate
MHz, CDCl
3
1
Reaction time 30 h, Yield: 59% (62 mg), Physical appearance: Pale-yellow
-
1
IR (KBr, cm ): 3034, 2978, 1714, 1651, 1486, 1455, 1372, 1268, 1164,
o
1
solid, M. p. 86-88 C, TLC R
400 MHz, CDCl ): δ 7.43 (d, J = 15.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H),
.33–7.17 (m, 4H), 6.92 (d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 6.15 (d, J = 15.8
Hz, 1H), 5.18 (s, 2H), 4.62 (s, 2H), 3.83 (s, 3H), 2.24 (s, 3H); 13C NMR (100
MHz, CDCl ): δ 169.9, 166.7, 159.7, 142.3, 137.4, 135.4, 131.9, 130.1,
28.8, 128.6, 128.1, 127.8, 125.8, 123.7, 118.4, 114.0, 66.3, 55.3, 41.2,
f
0.30 (7:3, Petroleum ether:EtOAc); H NMR
1
3
118, 982, 847, 756, 698, 618; ESI-HRMS: C22
70.1414, found 370.1415.
H21NO
3
Na [M+Na]+
(
7
3
Methyl (E)-3-(1-acetyl-6-methyl-1,2-dihydroquinolin-3-yl)acrylate (3f):
3
1
2
-
1
2.5; IR (KBr, cm ): 3469, 2957, 2838, 1645, 1515, 1487, 1372, 1250,
Na [M+Na]+
Reaction time 15 h, Yield: 65% (47 mg), Physical appearance: Pale yellow
solid, M. p. 115-117 oC, TLC R
NMR (400 MHz, CDCl
0.20 (4:1, Petroleum ether:EtOAc); 1
1163, 1033, 981, 845, 760, 527; ESI-HRMS: C
22 4
H21NO
f
H
386.1363, found 386.1361.
3
): δ 7.41 (d, J = 15.8 Hz, 1H), 7.16–6.99 (m, 3H),
.76 (s, 1H), 6.11 (d, J = 15.8 Hz, 1H), 4.62 (s, 2H), 3.80 (s, 3H), 2.36 (s,
H), 2.23 (s, 3H); 13C NMR (100 MHz, CD
Cl ): δ 170.0, 167.4, 142.3,
35.6, 135.0, 131.9, 129.2, 128.7, 128.3, 123.5, 118.0, 51.8, 41.0, 22.5,
6
3
1
2
3
3
Ethyl (E)-3-(1-acetyl-5-bromo-1,2-dihydroquinolin-3-yl)acrylate (3m):
-
1
0.8; IR (KBr, cm ): 3413, 2925, 1637, 1380, 1272, 1176, 831; ESI-HRMS:
Reaction time 15 h, Yield: 48% (33 mg), Physical appearance: Off-white
+
16 3
C H17NO Na [M+Na] 294.1101, found 294.1115.
solid, M. p. 153-155 oC, TLC R
0.25 (4:1, Petroleum ether:EtOAc); 1
f
H
NMR (500 MHz, CDCl
(d, J = 15.9 Hz, 1H), 4.61 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H),
.35 (t, J = 7.1 Hz, 3H);13C NMR (100 MHz, CD
Cl ): δ 169.8, 166.6, 141.7
2C), 138.9, 130.4, 130.0, 128.8, 128.6, 123.1, 122.7, 119.8, 60.7, 41.5,
3
): δ 7.58 – 7.37 (m, 2H), 7.26 – 7.12 (m, 3H), 6.19
Ethyl (E)-3-(1-acetyl-6-bromo-1,2-dihydroquinolin-3-yl)acrylate (3g):
1
(
3
3
Reaction time 15 h, Yield: 51% (36 mg), Physical appearance: Off-white
-
1
solid, M. p. 158-160 oC, TLC R
NMR (400 MHz, CDCl
0.25 (4:1, Petroleum ether:EtOAc); 1
22.5, 14.3; IR (KBr, cm ): 3378, 2980, 2925, 2768, 2089, 1856, 1180,
f
H
+
1035, 989; ESI-HRMS: C16H16BrNO
3
Na [M+Na] 372.0206 and 374.0186,
3
): δ 7.42 – 7.25 (m, 3H), 7.08 (s, 1H), 6.68 (bs, 1H),
.09 (d, J = 15.9 Hz, 1H), 4.57 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.19 (s,
H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl
): δ 170.0, 166.6,
41.4 (2C), 136.3, 131.1, 130.6, 130.2 (2C), 125.2, 119.7, 118.8, 60.7,
found 372.0189 and 374.0170.
6
3
1
4
1
3
(G) General procedure for the synthesis of 8-alkenyl-1,2-dihydro-N-
acetyl-quinolines:
-
1
1.2, 22.5, 14.3; IR (KBr, cm ): 3378, 2980, 2925, 2768, 2089, 1856, 1180,
035, 989; ESI-HRMS: C16 17BrNO
[M+H]+ 350.0366 and 352.0367,
H
3
found 350.0368 and 352.0351.
In a pressure tube equipped with a stir bar, N-acetyl-1,2-dihydroquinoline
(
0.3 mmol) in dry toluene (1.5 mL) was taken. The reaction mixture was
degassed for 10 min followed by the addition of [RuCl (p-cymene)] (0.015
mmol), AgSbF (0.060 mmol), Cu(OAc) (0.600 mmol) and olefin coupling
Ethyl (E)-3-(1-acetyl-6-chloro-1,2-dihydroquinolin-3-yl)acrylate (3h):
2
2
6
2
partner (0.600 mmol). The tube was fitted with Teflon screw cap under an
argon flow. The reaction mixture was heated to 100 C and allowed to stir
Reaction time 15 h, Yield: 46% (34 mg), Physical appearance: Off-white
o
solid, M. p. 160-162 oC, TLC R
0.25 (4:1, Petroleum ether:EtOAc); 1
f
H
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Chemistry - A European Journal
10.1002/chem.201904512
FULL PAPER
for about 14 h (total time). The progress of the reaction was monitored by
TLC. Upon cooling to room temperature, the reaction mixture was diluted
with EtOAc and filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and the crude product was purified
by silica gel flash column chromatography.
6.48 (d, J = 9.4 Hz, 1H), 6.31–6.20 (m, 1H), 5.76–5.62 (m, 1H), 3.82 (s,
3H), 1.83 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl
3
): δ
171.4, 166.9, 140.0, 135.8, 135.0, 131.2, 130.3, 127.8, 126.6, 125.8, 123.7,
-
1
119.8, 51.9, 47.1, 22.6, 16.5; IR (KBr, cm ): 3402, 2953, 1655, 1442, 1302,
1169, 1112, 1033, 813, 714, 601; ESI-HRMS: C16
Na [M+Na]+
94.1101, found 294.1114.
H17NO
3
2
Benzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4a):
Methyl (E)-3-(1-acetyl-6-nitro-1,2-dihydroquinolin-8-yl)acrylate (4f):
Reaction time 14 h, Yield: 73% (70 mg), Physical appearance: Brownish
o
1
solid, M. p. 93-95 C, TLC R
400 MHz, CDCl ): δ 7.80 (d, J = 16.0 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H),
.46–7.34 (m, 5H), 7.32–7.25 (m, 1H), 7.20 (d, J = 6.8 Hz, 1H), 6.66–6.51
f
0.30 (4:1, Petroleum ether:EtOAc); H NMR
Reaction time 14 h, Yield: 71% (49 mg), Physical appearance: Pale yellow
(
7
3
solid, M. p. 113-115 oC, TLC R 0.20 (7:3, Petroleum ether:EtOAc); 1
f
H
3
NMR (400 MHz, CDCl ): δ 8.42 (s, 1H), 8.02 (d, J = 14.7 Hz, 1H), 7.69 (d,
(
(
m, 2H), 6.31 – 6.23 (m, 1H), 5.53 (dd, J = 16.8, 5.8 Hz, 1H), 5.38–5.21
m, 2H), 3.54 (d, J = 16.8 Hz, 1H), 1.83 (s, 3H); 13C NMR (100 MHz,
J = 15.0 Hz, 1H), 6.70 (s, 2H), 6.42 (s, 1H), 5.60 (d, J = 13.2 Hz, 1H), 3.84
(s, 3H), 3.61 (d, J = 14.2 Hz, 1H), 2.49–1.74 (m, 3H); 13C NMR (100 MHz,
CDCl
3
): δ 171.7, 166.3, 140.5, 137.3, 135.9, 131.4, 131.0, 130.0, 128.6,
CDCl
3
): δ 170.8, 166.2, 145.9, 142.0, 138.2, 133.2, 132.4, 131.1, 125.2,
-
1
-1
128.3, 128.0, 126.8, 126.1, 125.7, 119.8, 66.5, 41.9, 22.0; IR (KBr, cm ):
122.3, 121.8, 120.5, 52.1, 42.1, 22.1; IR (KBr, cm ): 3372, 3081, 1720,
3
403, 3036, 1717, 1670, 1450, 1375, 1296, 1164, 994, 818, 753, 697, 602;
1677, 1528, 1441, 1346, 1316, 1274, 1210, 1178, 1044, 989, 794, 697;
+
+
ESI-HRMS: C21
3
H19NO Na [M+Na] 356.1257, found 356.1283.
14 2 5
ESI-HRMS: C15H N O Na [M+Na] 325.0795, found 325.0784.
Methyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4b):
Methyl
4g):
(E)-3-(1-acetyl-6-methyl-1,2-dihydroquinolin-8-yl)acrylate
(
Reaction time 14 h, Yield: 62% (46 mg), Physical appearance: Brown solid,
o
1
M. p. 71-73 C, TLC R
MHz, CDCl ): δ 7.75 (d, J = 16.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.34-
.26 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.61–6.49 (m, 2H), 6.31–6.24 (m,
H), 5.53 (dd, J = 16.8, 5.8 Hz, 1H), 3.83 (s, 3H), 3.54 (d, J = 16.8 Hz, 1H),
.83 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 171.8, 166.9, 140.1, 137.2,
31.3, 130.9, 130.0, 128.0, 126.8, 126.1, 125.6, 119.8, 51.9, 41.9, 22.0;
f
0.30 (3:2, Petroleum ether:EtOAc); H NMR (400
Reaction time 14 h, Yield: 61% (44 mg), Physical appearance: Brown gel,
TLC R ):δ
0.30 (7:3, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl
7.70 (d, J = 16.0 Hz, 1H), 7.41-7.25 (m, 2H), 7.00 (s, 1H), 6.56–6.44 (m,
2H), 6.22 (d, J = 7.8 Hz, 1H), 5.48 (dd, J = 16.7, 5.1 Hz, 1H), 3.80 (s, 3H),
3.49 (d, J = 16.7 Hz, 1H), 2.38 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz,
3
f
3
7
1
1
1
3
CDCl
3
): δ 171.9, 167.0, 140.2, 136.5, 134.9, 131.1, 130.7, 129.6, 128.9,
-
1
-1
IR (KBr, cm ): 3427, 2924, 2852, 1714, 1667, 1450, 1372, 1323, 1169,
038, 992, 818, 754, 601; ESI-HRMS: C15
Na [M+Na]+ 280.0944,
found 280.0960.
126.2, 125.9, 119.5, 51.8, 42.0, 21.9, 21.0; IR (KBr, cm ): 3417, 2952,
1
H15NO
3
1660, 1434, 1279, 1038, 942, 859, 813, 735, 699, 601; ESI-HRMS:
+
C
16
H
17NO
3
Na [M+Na] 272.1281, found 272.1295.
Ethyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4c):
Methyl
4h):
(E)-3-(1-acetyl-6-methoxy-1,2-dihydroquinolin-8-yl)acrylate
(
Reaction time 14 h, Yield: 55% (43 mg), Physical appearance: Colorless
o
1
solid, M. p. 55-57 C, TLC R
400 MHz, CDCl ): δ 7.72 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H),
.27 (t, J = 7.0 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.71–6.43 (m, 2H), 6.28–
f
0.30 (7:3, Petroleum ether:EtOAc); H NMR
Reaction time 14 h, Yield: 52% (37 mg), Physical appearance: Pale-yellow
1
(
3
gel, TLC R
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
):
7
6
3
δ 7.72 (d, J = 16.1 Hz, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.64–6.47 (m, 2H),
6.30–6.20 (m, 1H), 5.50 (dd, J = 16.8, 5.8 Hz, 1H), 3.82 (s, 3H), 3.51 (d, J
.22 (m, 1H), 5.51 (dd, J = 16.8, 5.4 Hz, 1H), 4.27 (q, J = 13.7, 6.7 Hz, 2H),
.52 (d, J = 16.8 Hz, 1H), 1.81 (s, 3H), 1.33 (t, J = 6.9 Hz, 4H); 13C NMR
= 16.8 Hz, 1H), 2.40 (s, 4H), 1.82 (s, 3H); 13C NMR (101 MHz, CDCl
3
): δ
(
1
100 MHz, CDCl
3
): δ 171.7, 166.5, 139.9, 137.2, 131.3, 130.9, 130.1,
171.6, 167.4, 142.3, 137.6, 137.0, 132.6, 132.2, 131.4, 130.5, 126.6, 125.3,
118.2, 51.7, 41.6, 21.2, 18.1; IR (KBr, cm ): 3404, 2952, 1708, 1661, 1449,
-
1
-1
27.9, 126.8, 126.1, 125.7, 120.3, 60.7, 41.9, 22.0, 14.3; IR (KBr, cm ):
3
C
425, 2983, 1658, 1274, 1172, 1039, 994, 851, 754, 602; ESI-HRMS:
1370, 1281, 1178, 1037, 994, 858, 735, 700, 601; ESI-HRMS:
+
+
16 3
H17NO Na [M+Na] 294.1101, found 294.1119.
16 4
C H17NO Na [M+Na] 310.1050, found 310.1026.
(
(
E)-methyl
4d):
3-(1-acetyl-3-methyl-1,2-dihydroquinolin-8-yl)acrylate
Ethyl (E)-3-(1-acetyl-5-bromo-1,2-dihydroquinolin-8-yl)acrylate (4i):
Reaction time 14 h, Yield: 50% (35 mg), Physical appearance: Brown gel,
f 3
TLC R ) δ
0.25 (4:1, Petroleum ether:EtOAc); 1H NMR (500 MHz, CDCl
Reaction time 14 h, Yield: 62% (45 mg), Physical appearance: Yellow gel,
TLC R ): δ
0.30 (7:3, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl
.71 (d, J = 16.1 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H),
.11 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 16.1 Hz, 1H), 6.27 (s, 1H), 5.26 (d, J
17.3 Hz, 1H), 3.79 (s, 3H), 3.47 (d, J = 16.5 Hz, 1H), 1.96 (s, 3H), 1.78
f
3
7.72 – 7.60 (m, 2H), 7.32 (d, J = 1.7 Hz, 1H), 6.62 – 6.44 (m, 2H), 6.36 –
6.29 (m, 1H), 5.53 (dd, J = 17.0, 5.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.53
(d, J = 17.0 Hz, 1H), 1.83 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101
7
7
=
MHz, CDCl
3
): δ 171.5, 166.1, 138.5, 136.1, 133.0, 132.4, 131.9, 130.4,
(
1
s, 3H); 13C NMR (100 MHz, CDCl
3
): δ 171.9, 167.0, 141.8, 140.4, 136.0,
32.2, 129.7, 127.2, 126.8, 124.6, 121.0, 119.6, 51.9, 46.2, 22.1, 21.90;
128.1, 125.2, 121.4, 120.2, 60.9, 41.9, 21.9, 14.3; IR (KBr, cm ): 3389,
-1
2754, 2877, 1508, 1453, 1420, 1300, 1080; ESI-HRMS: C16
[M+H] 350.0386 and 352.0367, found 350.0377 and 352.0360.
H17BrNO
3
-
1
+
IR (KBr, cm ): 3389, 3014, 1648, 1263, 1152, 1012, 987, 850, 765; ESI-
HRMS: C16
+
H18NO
3
[M+H] 272.1281, found 272.1264.
Ethyl (E)-3-(1-acetyl-6-chloro-1,2-dihydroquinolin-8-yl)acrylate (4j):
Methyl
(E)-3-(1-acetyl-2-methyl-1,2-dihydroquinolin-8-yl)acrylate
(
4e):
Reaction time 14 h, Yield: 47% (35 mg), Physical appearance: Yellow gel,
TLC R ): δ
0.25 (4:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl
f
3
Reaction time 14 h, Yield: 68% (49 mg), Physical appearance: Colorless
7.64 (d, J = 16.0 Hz, 1H), 7.50 (s, 1H), 7.16 (d, J = 1.7 Hz, 1H), 6.51 (d, J
= 15.4 Hz, 2H), 6.35 – 6.26 (m, 1H), 5.51 (dd, J = 17.0, 5.7 Hz, 1H), 4.27
(q, J = 7.0 Hz, 2H), 3.50 (d, J = 17.0 Hz, 1H), 1.81 (s, 3H), 1.33 (t, J = 7.1
o
1
solid, M. p. 96-98 C, TLC R
400 MHz, CDCl ): δ 7.67 (d, J = 16.1 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H),
.28 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 16.1 Hz, 1H),
f
0.30 (4:1, Petroleum ether:EtOAc); H NMR
(
3
7
Hz, 3H); 13C NMR (101 MHz, CDCl
3
): δ 171.5, 166.1, 138.6, 135.6, 132.8,
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Chemistry - A European Journal
10.1002/chem.201904512
FULL PAPER
1
32.5, 132.4, 131.6, 127.5, 125.1, 121.4, 60.9, 42.0, 21.9, 14.3; IR (KBr,
5.28–5.13 (m, 2H), 3.83 (s, 4H), 3.52 (d, J = 16.8 Hz, 1H), 1.81 (s, 3H); 13
NMR (100 MHz, CDCl ): δ 171.7, 166.4, 159.7, 140.4, 137.3, 131.3, 130.9,
130.2, 130.0, 128.1, 128.0, 126.8, 126.1, 125.7, 120.0, 114.0, 66.4, 55.3,
C
-
1
cm ): 3416, 2981, 2754, 2356, 2334, 1622, 1397, 1265, 1118, 1044, 748;
3
+
ESI-HRMS: C16
H
16ClNO
3
Na [M+Na] 328.0711, found 328.0728.
-
1
4
1
3
1.9, 22.0; IR (KBr, cm ): 3473, 2957, 1713, 1665, 1514, 1454, 1163,
+
034, 819, 753, 692; ESI-HRMS: C22
H21NO
4
Na [M+Na] 386.1363, found
Methyl (E)-3-(1-acetyl-3-bromo-1,2-dihydroquinolin-8-yl)acrylate (4k):
86.1366.
Reaction time 14 h, Yield: 65% (43 mg), Physical appearance: Colorless
o
1
3-Bromobenzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4p):
solid, M. p. 82-84 C, TLC R
400 MHz, CDCl ): δ 7.68 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H),
.31–7.22 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.86 (s, 1H), 6.50 (d, J = 16.0
Hz, 1H), 5.62 (d, J = 16.8 Hz, 1H), 3.78 (s, 3H), 1.80 (s, 3H); 13C NMR (100
MHz, CDCl ): δ 171.6, 166.8, 139.7, 135.3, 131.3, 130.4, 127.4, 127.2,
f
0.30 (4:1, Petroleum ether:EtOAc); H NMR
(
3
7
Reaction time 14 h, Yield: 52% (62 mg), Physical appearance: Colorless
o
1
solid, M. p. 92-94 C, TLC R
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR
3
(400 MHz, CDCl ): δ 7.80 (d, J = 16.0 Hz, 1H), 7.60-7.53 (m, 2H), 7.47 (d,
3
-
1
1
25.9, 123.7, 120.3, 52.0, 48.7, 22.0; IR (KBr, cm ): 3397, 2951, 1718,
J = 7.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.31-7.23 (m, 2H), 7.20 (d, J =
7.2 Hz, 1H), 6.65–6.51 (m, 2H), 6.25 (d, J = 7.2 Hz, 1H), 5.52 (dd, J = 16.8,
5.0 Hz, 1H), 5.32–5.15 (m, 2H), 3.53 (d, J = 16.8 Hz, 1H), 1.82 (s, 3H); 13
C
1
685, 1449, 1370, 1330, 1271, 1200, 1169, 1040, 860, 756, 564; ESI-
+
HRMS: C15
3
H14BrNO Na [M+Na] 358.0049 and 360.0029, found 358.0055
and 360.0037.
NMR (100 MHz, CDCl
3
): δ 171.7, 166.1, 140.9, 138.2, 137.4, 131.4, 131.1,
1
4
1
4
31.0, 130.2, 129.9, 128.1, 126.8, 126.7, 126.1, 125.7, 122.6, 119.4, 65.5,
-
1
2.0, 22.0; IR (KBr, cm ): 3460, 2932, 1702, 1653, 1530, 1472, 1186,
Ethyl (E)-3-(1-acetyl-5-bromo-1,2-dihydroquinolin-8-yl)acrylate (4l):
+
008, 912, 798, 678; ESI-HRMS: C21
H18BrNO
3
Na [M+Na] 434.0362 and
36.0343, found 434.0356 and 436.0339.
Reaction time 14 h, Yield: 47% (32 mg), Physical appearance: Brown gel,
TLC R
f
0.25 (4:1, Petroleum ether:EtOAc); 1H NMR (500 MHz, CDCl
3
) δ
(
H) Synthesis of quinoline-3-d (6a’):19
7
6
1
1
.68 (d, J = 16.1 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H),
.92 (dd, J = 9.6, 1.9 Hz, 1H), 6.54 (d, J = 16.1 Hz, 1H), 6.44 – 6.38 (m,
H), 5.52 (dd, J = 17.0, 5.8 Hz, 1H), 4.29 (q, J = 6.9 Hz, 2H), 3.49 (d, J =
6.9 Hz, 1H), 1.83 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
In a pressure tube equipped with a stir bar, 3-bromoquinoline (0.966 mmol)
was dissolved in dry toluene (4 mL). The reaction mixture was degassed
CDCl
3
): δ 171.5, 166.3, 139.1, 138.4, 132.9, 131.0, 130.7, 129.7, 126.1,
for 10 min followed by the addition of Pd(OAc)
2 3
(5 mol%), PCy (10 mol%),
-
1
1
2
3
25.4, 123.2, 120.8, 60.9, 41.5, 22.0, 14.3; IR (KBr, cm ): 3389, 2754,
677, 1508, 1453, 1420, 1300, 1080; ESI-HRMS: C16
50.0386 and 352.0367, found 350.0377, 352.0360.
K
3
PO (1.449 mmol), and CD OD (0.8 mL). The tube was fitted with Teflon
4
3
H17BrNO
3
[M+H]+
screw cap under an argon flow. The reaction mixture was stirred at 80 °C
for 12 h. The progress of the reaction was monitored by GC-MS. Upon
cooling to room temperature, the reaction mixture was diluted with EtOAc
and filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure and the crude product was purified by silica gel flash
4-Nitrobenzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4m):
column chromatography. The title compound was isolated as a pale-yellow
Reaction time 14 h, Yield: 71% (78 mg), Physical appearance: Brown solid,
1
o
1
gel (75% yield, 94 mg). H NMR (400 MHz, CDCl
3
) δ 8.92 (s, 1H), 8.20 –
M. p. 135-137 C, TLC R
MHz, CDCl ): δ 8.27 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 16.0 Hz, 1H), 7.59 (d,
J = 8.4 Hz, 3H), 7.35–7.27 (m, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.69–6.53 (m,
H), 6.36–6.21 (m, 1H), 5.52 (dd, J = 16.8, 5.5 Hz, 1H), 5.37 (s, 2H), 3.56
d, J = 16.8 Hz, 1H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 171.7,
66.0, 147.7, 143.2, 141.3, 137.4, 131.4, 130.9, 129.7, 128.5, 128.3, 126.9,
f
0.20 (7:3, Petroleum ether:EtOAc); H NMR (400
8.07 (m, 2H), 7.81 (d, J = 8.1 Hz, 1H), 7.76-7.66 (m, 1H), 7.54 (t, J = 7.5
3
Hz, 1H). Spectral data obtained were in good agreement with those
reported in the literature.19
2
(
3
Quinoline-8-d (7a’):
1
1
2
-
1
26.1, 125.7, 123.9, 119.0, 65.0, 42.0, 22.0; IR (KBr, cm ): 3484, 3053,
218, 1732, 1668, 1447, 1373, 1212, 1171, 981, 808, 751, 607; ESI-
Prepared according to the general procedure (H) on a 200 mg scale and
the title compound was isolated as a pale-yellow gel (81 % yield, 101 mg).
+
HRMS: C21
H N O
18 2 5
Na [M+Na] 401.1108, found 401.1137.
1H NMR (400 MHz, CDCl
7
7
) δ 8.95 – 8.84 (m, 1H), 8.13 (d, J = 8.3 Hz, 1H),
.79 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 6.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H),
.36 (dd, J = 8.0, 4.0 Hz, 1H). Spectral data obtained were in good
3
4-Chlorobenzyl (E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate (4n):
20
agreement with those reported in the literature.
Reaction time 14 h, Yield: 67% (71 mg), Physical appearance: Colorless
solid, M. p. 121-123 oC, TLC R 0.20 (4:1, Petroleum ether:EtOAc); 1
NMR (400 MHz, CDCl ): δ 7.80 (d, J = 16.2 Hz, 1H), 7.55 (d, J = 7.8 Hz,
H), 7.41–7.34 (m, 4H), 7.32–7.26 (m, 1H), 7.21 (d, J = 6.8 Hz, 1H), 6.66–
f
H
1-(quinolin-1(2H)-yl-3-d)ethan-1-one (6a):
3
1
6
5
.52 (m, 2H), 6.32–6.24 (m, 1H), 5.53 (dd, J = 16.9, 5.8 Hz, 1H), 5.30 –
.17 (m, 2H), 3.55 (d, J = 16.9 Hz, 1H), 1.82 (s, 3H); 13C NMR (100 MHz,
Prepared according to the general procedure (A) on 90 mg scale and the
title compound was isolated as a pale-yellow gel (78 % yield, 94 mg). TLC
1
CDCl
3
): δ 171.7, 166.2, 140.8, 137.3, 134.4, 134.2, 131.4, 131.0, 129.9,
R
f
0.30 (3:2, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
): δ 7.33
1
29.7, 128.8, 128.1, 126.8, 126.1, 125.7, 119.6, 65.7, 42.0, 22.0; IR (KBr,
– 7.07 (m, 4H), 6.54 (s, 1H), 4.48 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz,
-
1
cm ): 3415, 3052, 2888, 1714, 1667, 1451, 1372, 1274, 1162, 1096, 1013,
CDCl
3
): δ 170.1, 150.3,137.0, 136.0, 129.5, 127.1, 126.4, 125.7, 123.9,
851, 753, 815, 692; ESI-HRMS: C21
H19ClNO
3
[M+H]+ 368.1048, found
41.3, 22.4; IR (KBr, cm ): 3342, 2909, 1635, 1462, 1353, 1178, 1130, 875,
760; ESI-HRMS: C11
-1
+
368.1067.
H
10DNONa [M+Na] 197.0796, found 197.0770.
4-Methoxybenzyl
(E)-3-(1-acetyl-1,2-dihydroquinolin-8-yl)acrylate
1-(quinolin-1(2H)-yl-8-d)ethan-1-one (7a):
(4o):
Prepared according to the general procedure (A) on 100 mg scale and the
Reaction time 14 h, Yield: 62% (65 mg), Physical appearance: Colorless
title compound was isolated as a pale-yellow gel (81 % yield, 108 mg). TLC
o
1
1
solid, M. p. 77-79 C, TLC R
400 MHz, CDCl ): δ 7.77 (d, J = 16.1 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H),
.37 (d, J = 8.0 Hz, 2H), 7.31–7.14 (m, 3H), 6.92 (d, J = 8.0 Hz, 2H), 6.66–
.46 (m, 2H), 6.25 (d, J = 7.2 Hz, 1H), 5.51 (dd, J = 16.8, 5.3 Hz, 1H),
f
0.20 (4:1, Petroleum ether:EtOAc); H NMR
R
f
0.30 (3:2, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl
3
): δ 7.25
(
3
– 7.09 (m, 3H), 6.54 (d, J = 9.4 Hz, 1H), 6.17 – 6.05 (m, 1H), 4.47 (s, 2H),
2.22 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 170.1, 150.3, 136.2, 129.4,
127.8, 127.0, 126.4, 125.6, 121.1, 41.4, 22.4; IR (KBr, cm ): 3285, 2879,
7
6
3
-
1
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Chemistry - A European Journal
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FULL PAPER
1
632, 1456, 1350, 11200, 1143, 912, 776; ESI-HRMS: C11
H
11DNO [M+H]+
Reaction time 8 h, Yield: 81% (7 mg), Physical appearance: Brown solid,
o
0.30 (4:1, Petroleum ether:EtOAc); 1H NMR (400
175.0976, found 175.0981.
M. p. 88-90 C, TLC R
f
MHz, CDCl
3
): δ 9.04 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.85 (d,
J = 16.0 Hz, 1H), 7.65-7.58 (m, 2H), 6.67 (d, J = 16.0 Hz, 1H), 3.87 (s, 3H),
(
I) General procedure for aromatization of alkenyl-1,2-dihydro-N-
2
1
.57 (s, 3H); 13C NMR (100 MHz, CDCl
37.6, 135.2, 133.2, 128.8, 127.7, 127.4, 127.2, 119.6, 51.9, 21.6; IR (KBr,
3
): δ 166.9, 148.1, 146.9, 141.5,
acetyl-quinolines:
-
1
cm ): 2921, 1723, 1236, 1436, 1315, 1264, 1175, 980, 860, 818, 540; ESI-
In a round-bottom flask, alkenyl-1,2-dihydro-N-acetyl-quinoline (0.050
mmol) was dissolved in 1,4-dioxane (1 mL), followed by addition of DDQ
+
HRMS: C14
H
14NO
2
[M+H] 228.1019 found 228.1014.
(
0.15 mmol). The reaction mixture was refluxed for 2-8 h (total time). The
Methyl (E)-3-(quinolin-8-yl)acrylate (17f)
progress of reaction was monitored by TLC. Upon cooling to room
temperature, the reaction mixture was diluted with EtOAc and washed
twice with brine solution. The organic extract was dried over anhydrous
Na SO , filtered and concentrated under reduced pressure. The crude
2 4
product was purified by silica gel flash column chromatography.
Prepared according to the general procedure (E) on 10 mg scale and the
title compound was isolated as a pale-yellow gel (88% yield, 7 mg).
Reaction time was 2 h. 1H NMR (400 MHz, CDCl
3
) δ 9.02 (dd, J = 4.2, 1.8
Hz, 1H), 8.94 (d, J = 16.1 Hz, 1H), 8.21 (dd, J = 8.3, 1.8 Hz, 1H), 8.02 (dd,
J = 7.3, 0.9 Hz, 1H), 7.89 (dd, J = 8.2, 1.3 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H),
Methyl (E)-3-(quinolin-3-yl)acrylate (17a):
7.49 (dd, J = 8.3, 4.2 Hz, 1H), 6.85 (d, J = 16.1 Hz, 1H), 3.88 (s, 3H).
Spectral data obtained were in good agreement with those reported in the
literature.11b
Prepared according to the general procedure (E) on 10 mg scale and the
title compound was isolated as a pale-yellow gel (75% yield, 6 mg).
1
Reaction time was 2 h. H NMR (400 MHz, CDCl
3
) δ 9.12 (s, 1H), 8.27 (d,
4-Nitrobenzyl (E)-3-(quinolin-8-yl)acrylate (17g):
J = 1.9 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.97 – 7.84 (m, 2H), 7.82 – 7.75
m, 1H), 7.64 − 7.59 (m, 1H), 6.70 (d, J = 16.1 Hz, 1H), 3.88 (s, 3H).
(
Spectral data obtained were in good agreement with those reported in the
literature.21
Reaction time 2 h, Yield: 91% (8 mg), Physical appearance: Pale-yellow
solid, M. p. 120-122 oC, TLC R 0.40 (4:1, Petroleum ether:EtOAc); 1
NMR (400 MHz, CDCl ): δ 9.07–8.94 (m, 2H), 8.27 (d, J = 8.2 Hz, 2H),
.21 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H),
.66-7.58 (m, 3H), 7.50 (dd, J = 8.2, 4.2 Hz, 1H), 6.96 (d, J = 16.2 Hz, 1H),
.42 (s, 2H); 13C NMR (100 MHz, CD
Cl ): δ 166.6, 150.4, 146.3, 143.7,
42.5, 136.4, 132.8, 130.5, 128.5, 128.4, 128.4, 126.3, 123.8, 121.7, 119.6,
f
H
3
8
7
5
1
6
7
4-Nitrobenzyl (E)-3-(quinolin-3-yl)acrylate (17b):
3
3
Reaction time 2 h, Yield: 92% (8 mg), Physical appearance: Pale-yellow
solid, M. p. 123-125 oC, TLC R 0.30 (3:2, Petroleum ether: EtOAc); 1
NMR (400 MHz, CDCl ): δ 9.13 (s, 1H), 8.28 (d, J = 8.4 Hz, 3H), 8.14 (d,
f
H
-
1
4.8; IR (KBr, cm ): 3380, 2923, 1715, 1603, 1520, 1348, 1267, 1061, 978,
3
+
90, 736, 601; ESI-HRMS: C19
H N
15 2
O
4
[M+H] 335.1026, found 335.1025.
J = 8.4 Hz, 1H), 7.93 (d, J = 16.2 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.79 (t,
J = 7.6 Hz, 1H), 7.62 (d, J = 8.2 Hz, 3H), 6.76 (d, J = 16.2 Hz, 1H), 5.40 (s,
H); 13C NMR (100 MHz, CDCl
Methyl (E)-3-(6-methylquinolin-8-yl)acrylate (17h):
2
1
3
): δ 165.9, 149.1, 148.7, 147.8, 143.1,
42.6, 135.9, 130.9, 129.4, 128.5, 128.4, 127.6, 127.1, 123.9, 119.0, 65.1;
-
1
IR (KBr, cm ): 3406, 2922, 1712, 1614, 1506, 1351, 1263, 1174, 973, 860,
Reaction time 8 h, Prepared according to the general procedure (E) on 10
+
674; ESI-HRMS: C19H N O
15 2 4
[M+H] 335.1026, found 335.1038.
mg scale and the title compound was isolated as a brown gel (83% yield,
1
7
mg). H NMR (400 MHz, CDCl
3
) δ 8.99 – 8.82 (m, 2H), 8.12 (d, J = 8.2
Hz, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.45 (dd, J = 8.0, 4.0 Hz, 1H), 6.83 (d,
J = 16.2 Hz, 1H), 3.87 (s, 3H), 2.58 (s, 3H). Spectral data obtained were
in good agreement with those reported in the literature.11b
4
-Methoxybenzyl (E)-3-(quinolin-3-yl)acrylate (17c):
Reaction time 2 h, Yield: 87% (8 mg), Physical appearance: Brown solid,
M. p. 76-78 C, TLC R
o
0.30 (4:1, Petroleum ether:EtOAc); 1H NMR (400
f
Methyl (E)-3-(6-nitroquinolin-8-yl)acrylate (17i):
MHz, CDCl
3
): δ 9.13 (bs, 1H), 8.26 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H), 7.88
d, J = 15.8 Hz, 2H), 7.78 (t, J = 6.4 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.40
d, J = 7.8 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 6.71 (d, J = 16.0 Hz, 1H), 5.24
s, 2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 166.3, 159.8, 141.5,
35.7, 130.8, 130.8, 130.3, 129.4, 128.5, 128.4, 127.9, 127.6, 120.1, 114.1,
(
(
(
Reaction time 8 h, Yield: 87% (7 mg), Physical appearance: Pale-yellow
solid, M. p. 164-166 oC, TLC R 0.30 (4:1, Petroleum ether:EtOAc); 1
H
3
f
1
6
1
3
NMR (400 MHz, CDCl ): δ 9.20–9.13 (m, 1H), 8.90 (d, J = 16.2 Hz, 1H),
8.82 (s, 1H), 8.75 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.2, 4.0
Hz, 1H), 6.93 (d, J = 16.2 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz,
-
1
6.5, 55.3; IR (KBr, cm ): 3397, 2928, 2376, 1709, 1623, 1305, 1252,
165, 1034, 981, 861, 756; ESI-HRMS: C20
[M+H]+ 320.1281,
H18NO
3
found 320.1290.
-Chlorobenzyl (E)-3-(quinolin-3-yl)acrylate (17d):
Reaction time 2 h, Yield: 83% (7 mg), Physical appearance: Brown solid,
3
CDCl ): δ 166.8, 153.4, 147.9, 145.2, 139.1, 138.2, 135.5, 127.6, 125.5,
-
1
1
1
2
23.3, 122.8, 120.6, 52.0; IR (KBr, cm ): 3386, 2922, 1716, 1600, 1350,
271, 993, 879, 788; ESI-HRMS: C13
59.0697
11 2 4
H N O
[M+H]+ 259.0713, found
4
o
0.30 (4:1, Petroleum ether:EtOAc); 1H NMR (400
Methyl (E)-3-(3-bromoquinolin-8-yl)acrylate (17j):
M. p. 93-95 C, TLC R
MHz, CDCl ): δ 9.11 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.98–
.84 (m, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.39 (s, 4H),
.72 (d, J = 16.0 Hz, 1H), 5.27 (s, 2H); 13C NMR (100 MHz, CDCl
): δ 166.1,
49.1, 148.6, 142.0, 135.7, 134.3, 130.8, 129.8, 129.4, 128.9, 128.6, 128.4,
f
3
7
6
1
1
1
Reaction time 8 h, Yield: 81% (7 mg), Physical appearance: Colorless solid,
o
1
3
M. p. 66-68 C, TLC R
MHz, CDCl ): δ 8.98 (s, 1H), 8.85 (d, J = 16.2 Hz, 1H), 8.34 (s, 1H), 8.01
(d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 6.83
(d, J = 16.2 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl
): δ 167.4,
151.2, 144.2, 140.5, 137.4, 133.4, 129.4, 129.0, 128.2, 127.5, 120.7, 118.0,
5
1
2
f
0.40 (4:1, Petroleum ether:EtOAc); H NMR (400
3
-
1
27.6, 127.5, 127.3, 119.6, 65.8; IR (KBr, cm ): 3401, 2927, 2376, 1718,
630, 1260, 1181, 978, 864, 814, 755, 550; ESI-HRMS: C19
H
15ClNO
2
3
+
[M+H] 324.0786, found 324.0806.
-
1
1.8; IR (KBr, cm ): 3406, 3063, 2950, 2919, 2850, 1715, 1634, 1435,
366, 1311, 1172, 1084, 899, 768, 570; ESI-HRMS: C13
91.9968 and 293.9948, found 291.9955 and 293.9934.
H11BrNO
2
[M+H]+
Methyl (E)-3-(6-methylquinolin-3-yl)acrylate (17e):
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
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FULL PAPER
Acknowledgements
1
9, 11837; t) W. Liu, X. Yu, Y. Liab, C. Kuang, Chem. Commun. 2014,
0, 9291; u) Y. Shen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang, H. Wu,
5
Chem. Commun. 2014, 50, 4292; v) D. Xue, Z.-H. Jia, C.-J. Zhao, Y.-Y.
Zhang, C. Wang, J. Xiao, Chem. -Eur. J. 2014, 20, 2960. For selected
reviews on functionalizations of quinolines and other aza-heterocycles
via the Minisci-type reactions, see (w) R. S. J. Proctor, R. J. Phipps,
Angew. Chem. Int. Ed. 2019, 58, (doi: 10.1002/anie.201900977); Angew.
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SERB-India
(EMR/2016/004298)
and
CSIR-India
(
02(0361)/19/EMR-II) are gratefully acknowledged for the
research funding. R.D. and N.P.K. thank UGC-India and CSIR-
India respectively for Research Fellowships. A.S.D. thanks IISER
Bhopal for a fellowship. We thank the CIF, IISERB for the
analytical data. We also thank the Director, IISERB, for funding
and infrastructure facilities. We thank Prof. Saptarshi Mukherjee,
IISERB, for the assistance in the rate studies. We thank the
reviewers for their insightful suggestions.
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Chemistry - A European Journal
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Entry for the Table of Contents
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Riki Das, Nandkishor Prakash Khot,
Akanksha Santosh Deshpande and
Manmohan Kapur *
Page No. – Page No.
Catalyst-control in Switching the Site-
Selectivity of C−H Olefinations of 1,2-
dihydroquinolines: An Approach to
Positional-selective Functionalization
of Quinolines
A unique approach to achieve site-selective C−H olefinations exclusively at the C-3 or C-8 positions in the quinoline framework has
been developed via catalyst-control. Distal C(3)−H functionalization is achieved using palladium catalysis whereas, proximal C(8)−H
functionalization is obtained by employing ruthenium catalysis. Switching site-selectivity within a single substrate directly indicates
two diverse pathways which are operating in the palladium and ruthenium-catalyzed reaction conditions.
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