A Heck reaction/photochemical alkene isomerization sequence to prepare functionalized quinolines

Article abstract of DOI:10.1016/j.tet.2020.131396

A route to prepare functionalized quinolines based on a Heck reaction/UV-induced alkene isomerization sequence is described. The method allows for the preparation of quinolines under mild and neutral conditions and has broad functional group tolerance. Acid-sensitive functional groups that would not be tolerated under previous approaches can be included and a one-pot quinoline forming procedure is also reported.

Full text of DOI:10.1016/j.tet.2020.131396

Journal Pre-proof
A Heck reaction/photochemical alkene isomerization sequence to prepare
functionalized quinolines
Alex Kelly, Jack B. Hoffman, Oskar Hoff, Johannes C.L. Walker, Simon Werrel,
Timothy J. Donohoe
PII:
S0040-4020(20)30558-5
https://doi.org/10.1016/j.tet.2020.131396
TET 131396
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 May 2020
Revised Date: 7 July 2020
Accepted Date: 8 July 2020
Please cite this article as: Kelly A, Hoffman JB, Hoff O, Walker JCL, Werrel S, Donohoe TJ, A Heck
reaction/photochemical alkene isomerization sequence to prepare functionalized quinolines, Tetrahedron
(2020), doi: https://doi.org/10.1016/j.tet.2020.131396.
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Graphical Abstract
A Heck Reaction/Photochemical Alkene
Isomerization Sequence to Prepare
Functionalized Quinolines
Leave this area blank for abstract info.
Alex Kellya, Jack B. Hoffmana, Oskar Hoffa, Johannes C. L. Walkera,b, Simon Werrela and Timothy J. Donohoea
a Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom
b Current address: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen,
Tammannstr. 2, 37077 Göttingen, Germany

1
Tetrahedron
journal homepage: www.elsevier.com
A Heck Reaction/Photochemical Alkene Isomerization Sequence to Prepare
Functionalized Quinolines
Alex Kellya, Jack B. Hoffmana, Oskar Hoffa, Johannes C. L. Walkera,b, Simon Werrela and Timothy J.
Donohoea
a Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom.
b Current address: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany.
Dedicated to Professor Richard Taylor.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A route to prepare functionalized quinolines based on a Heck reaction/UV-induced alkene
isomerization sequence is described. The method allows for the preparation of quinolines under
mild and neutral conditions and has broad functional group tolerance. Acid-sensitive functional
groups that would not be tolerated under previous approaches can be included and a one-pot
quinoline forming procedure is also reported.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Heck reactions
Photochemical isomerization
Quinolines
1. Introduction
metathesis/photochemical isomerization approach for the rapid
synthesis of functionalized furans and pyrroles (Scheme 1,
bottom).[10] A number of acid-sensitive functionalities could be
incorporated into the target using the mild photochemical
conditions and we wondered whether a similar strategy could
also be applied to quinoline synthesis.[11]
Quinolines are key motifs found within a variety of natural
products[1] and bioactive compounds,[2] and are generally
valuable intermediates in organic synthesis. Traditional routes to
quinolines include the venerable Skraup, Combes, Doebner–
Miller and Friedlander syntheses.[3] However, each of these
methods has their limitations, namely poor functional group
tolerance arising from the harsh reaction conditions, poor
selectivity, or low yields.[3] This situation has led to an extensive
search for new approaches to prepare quinolines, with many
ingenious disconnections now available.[4] One strategy reported
by Heck and co-workers used a palladium-catalyzed coupling
reaction between an ortho-iodoaniline and dimethyl maleate to
arrive at the corresponding quinolone derivative (Scheme 1,
top).[5] Later, Larock and co-workers disclosed a related approach
using allyl alcohols as the Heck reaction partner,[6] which
proceeded first via the β-aryl ketone to provide a cyclized
dihydroquinoline, and then exploited their in-situ Pd(0)-catalyzed
dehydrogenation to form the desired quinolines in moderate
yields. These reports were the starting point for a series of
innovative approaches to quinoline synthesis based around the
disconnection provided by the Heck reaction.[7] Alternative
methods of accessing similar β-aryl ketone-type intermediates
have also been reported in the context of quinoline synthesis.[8]
Our plan was to perform a Heck reaction[12] between readily
available ortho-bromoanilines (in contrast to the less common
ortho-iodoanilines which are conventionally used) and enones to
access β-aryl-α,β-unsaturated ketones. These would then be
subjected to our previous photochemical alkene isomerization
conditions to allow formation of the desired quinolines.[13–16] The
direct use of enone derivatives in the Heck reaction would
circumvent the need for an oxidation step, and the mild
photochemical isomerization conditions would hopefully allow
for the incorporation of a variety of functionality, overcoming the
issues of limited substrate scope and harsh conditions of previous
methods. However, it should be noted that the Heck reaction
between ortho-haloanilines and enones is rare. During the course
of our investigation, a report by Wang, Zhai and co-workers
reported the isomerization of similar β-aryl-α,β-unsaturated
ketone intermediates to quinolines using blue LEDs.[17] No
general access to these key intermediates was reported, although
some were prepared via Heck reaction with ortho-iodoanilines.
Herein, we report our results to complement their publication.
Our group has a longstanding interest in the application of
catalytic transformations for the de-novo synthesis of aromatic
heterocycles.[9]
We
recently
reported
an
alkene

2
Tetrahedron
a
Table 1. Optimization of the Heck reaction. Yield of isolated
material
modification to
reaction conditions
yield 3aa
entry
1
base
time
5 h
(%)a
2.5 equiv 1a, 1.0
equiv 2a
41
Cy2NMe
2
3
4
5
6
Cy2NMe
Cy2NMe
iPr2NEt
iPr2NEt
iPr2NEt
5 h
5 h
–
100 °C
72
33
91
64
31
–
20 h
20 h
20 h
1.5 equiv 2a
2-chloroaniline
2.2. Heck Reaction Substrate Scope
With optimized conditions in hand, we proceeded to investigate
the scope of the Heck reaction. In some cases, trace quantities
1
(<5%) of the cyclized quinoline were also detected in the H
NMRs of the crude reaction mixtures, but these were not isolated.
Pleasingly, a range of substituted ortho-bromoanilines were
tolerated in moderate to excellent yields (Scheme 2). ortho-
Bromoanilines incorporating additional halogen substituents
including fluorine (to give 3ba) and chlorine (to give 3ca)
provided the corresponding quinolines in 68% and 66% yield
respectively. A substrate containing the electron-withdrawing
trifluoromethyl group gave compound 3da in 52% yield.
Carbonyl-based functional groups were also well tolerated, with
ketone-containing 3ea formed in 78% yield and methyl ester-
containing 3fa isolated in 46% yield.
Scheme 1. Approaches to functionalized quinolines. HMPA =
hexamethylphosphoramide, PG = protecting group.
2. Results and discussion
2.1. Heck reaction optimization
We began by studying the reaction between ortho-bromoaniline
(1a) and benzylideneacetone (2a). Using Heck reaction
conditions based on those reported by Fu and co-workers, aniline
(E)-3aa could be isolated in 41% yield (Table 1, entry 1).[18]
Reversing the stoichiometry to make ortho-bromoaniline (1a) the
limiting reagent led to an improved yield of 72% (entry 2).
However, raising the temperature of the reaction resulted in a
large reduction in yield (entry 3). Switching to iPr2NEt as base
provided aniline 3aa in 91% isolated yield (entry 4). Neither
reducing the excess of enone 2a nor switching to 2-chloroaniline
as the limiting reagent led to any further improvement (entries 5
and 6). Note that the (E)-geometry of enone 3aa was verified by
nOe enhancements (see Supporting Information). Compound (Z)-
1
3aa was not observed in the H NMRs of the crude reaction
mixtures, although trace quantities of the cyclized quinoline
(<5%) were occasionally found. We presume that if compound
(Z)-3aa did form during the course of the reaction it is likely that
cyclization to the corresponding quinoline would occur
spontaneously.

3
Scheme 3. Scope of Heck reaction: variation of the enone 2. (a)
reaction conditions: Pd2(dba)3 (5.0 mol %), tBu3PHBF4
(20 mol %), iPr2NEt (3.0 equiv), PhMe (0.10 M), 80 ºC, 20 h.
Interestingly, on a number of occasions, we were surprised to
find that the quinoline was in fact the sole product from the Heck
reaction; none of the expected enone was observed (Scheme 4).
Enones 2h-i bearing aliphatic substituents at the β-position (R3 =
aliphatic) reacted to afford quinolines 4ah and 4ai in 81% and
39% yield. Enone 2j, with an ester group (R2) adjacent to the
carbonyl also led directly to quinoline 4aj, which was isolated in
52% yield. The substrates in these particular cases were all
electronically distinct from those previously discussed in that the
alkene lacked a conjugating aryl group at R3 (4ah, 4ai) or
possessed an activating R2 group (4aj). We suggest that these
factors may activate the initial Heck alkene product towards
reversible addition reactions and thus lead to isomerisation, and
cyclisation, during the Heck reaction itself.[19]
Scheme 2. Scope of Heck reaction: variation of ortho-
bromoaniline 1. (a) reaction conditions: Pd2(dba)3 (5.0 mol %),
tBu3PHBF4 (20 mol %), iPr2NEt (3.0 equiv), PhMe (0.10 M), 80
ºC, 20 h. The (E) geometry of compounds 3ba-3ha was assigned
by analogy to 3aa.
Some acid-sensitive functional groups including nitriles and
silyl ethers could also be incorporated to produce 3ga and 3ha in
92% and 67% yield respectively. These functional groups would
likely be troublesome under the harsher reactions conditions
typical of quinoline synthesis. Unfortunately, reactions with nitro
and methoxy-substituted ortho-bromanilines failed, providing
only complex reaction mixtures.
Variation of the enone component was also investigated (Scheme
3). Increased substitution at the α-position of the carbonyl was
possible giving 3ab in 54% yield. Alternatively, electron-rich
substituents could be incorporated on the β-aryl ring; 3ac and
3ad were each formed in 65% yield. Unfortunately, substrates
containing basic functionality such as amines (as in 2e) or
pyridines (as in 2f) were not amenable to the reaction, with no
reactivity observed. Presumably these relatively unhindered basic
species coordinated to the palladium catalyst, shutting down the
reaction. Aldehyde species were also not compatible; no reaction
was observed with cinnamaldehyde (2g).
Scheme 4. Scope of Heck reaction: direct formation of
quinolines. (a) reaction conditions: Pd2(dba)3 (5.0 mol %),
tBu3PHBF4 (20 mol %), iPr2NEt (3.0 equiv), PhMe (0.10 M), 80
ºC, 20 h.
2.3. Photochemical alkene isomerization
We then turned to the isomerization of the Heck reaction
products, which we hoped would furnish the target quinolines.
The UV-Vis absorption spectra of 3aa demonstrated that, as
before,[10] the enone intermediates absorbed in the 300–400 nm
range and should be able to absorb at the wavelength provided by

4
Tetrahedron
a
commercially available 365 nm Pen-Ray source (see
manipulation required was the addition of extra toluene to allow
Supporting Information for UV-Vis spectra).[20] We were
delighted to find that all of the Heck reaction products could
indeed be isomerized and cyclized to the corresponding
for efficient irradiation. The crude Heck reaction mixture was
thus cooled to 0 °C, once the reaction was complete, and then
diluted with more toluene before being irradiated at 365 nm to
afford the corresponding quinolines (Scheme 6). The one-pot
procedure generally compares favourably to the previous two-pot
approach. Quinoline 4aa was isolated in 89% yield compared to
79% previously. Using the one-pot method, quinolines 4ea and
4fa were also isolated in higher yields than before. Only nitrile-
containing quinoline 4ga was isolated in a slightly lower 83%
yield (90% previously).
o
quinolines in high yields at 0 C (Scheme 5). None of the enones
we had prepared failed to react. Model enone 3aa was converted
to quinoline 4aa in 87% yield. Halogen substituted enones 3ba
and 3ca gave quinolines 4ba and 4ca in 94% and 81% yields
respectively. Trifluoromethyl-substituted quinoline 4da could be
accessed in 79% yield. Quinolines incorporating carbonyl groups
(4ea, 4fa) were also prepared in 95% and 72% yields. The acid-
sensitive nitrile and silyl ether functional groups were tolerated
extremely well under the mild photochemical conditions to afford
quinolines 4ga and 4ha in 98% and 94% yield respectively.
Quinolines with differently functionalized heterocyclic rings
were also formed, with quinoline 4ab isolated in 74% yield and
aryl ether substituted quinolines 4ac and 4ad in 91% and 76%
yield respectively.
Ph
O
Br
O
R1
Me
R1
Ph
Me
Heck
NH2
reactiona
NH2
1
2a
(2.5 equiv)
3
Cooled to 0 °C
and diluted with PhMe
Ph
R3
O
R3
Photochemical
Me isomerizationb
R
365 nm
R2
N
R1
R1
PhMe, 0 °C
17 h
4
N
R2
NH2
3
4
Ph
O
Ph
Me
Variation of the carbocyclic ring
Ph
Ph
Ph
N
Me
N
Me
F
4aa
4ea
: 76%
: 89%
two-pot procedure (79%)
two-pot procedure (74%)
N
Me
N
Me
Cl
N
Me
Me
Ph
Ph
4aa
4ba
4ca
: 81%
: 87%
: 94%
NC
Ph
O
Ph
Ph
MeO
N
Me
N
Me
Me
Ph
O
MeO
4fa
4ga
: 83%
two-pot procedure (90%)
: 78%
two-pot procedure (33%)
CF3
N
Me
N
Me
N
Me
O
4da
4ea
4fa
: 72%
: 79%
: 95%
Scheme 6. One-pot Heck reaction/photochemical alkene
isomerization to quinolines. (a) Heck reaction conditions:
Pd2(dba)3 (5.0 mol %), tBu3PHBF4 (20 mol %), iPr2NEt (3.0
equiv), PhMe (0.10 M), 80 ºC, 20 h. (b) Photochemical alkene
isomerization reaction conditions: 365 nm, PhMe (10 µM), 0 ºC,
20 h.
Ph
NC
TESO
OMe
N
Me
N
Me
O
4ga
4ha
: 98%
: 94%
Variation of the heterocyclic ring
O
3. Conclusion
Ph
In summary, we have developed a route to functionalized
quinolines based on a Heck reaction/photochemical alkene
isomerization sequence. Compared with previous reports, the
advantages of this approach include the direct use of enones in
the Heck reaction, removing the need for an oxidation step, and
the use of the more available ortho-bromoanilines as reaction
partners. Photochemical alkene isomerization provides a means
of converting the Heck intermediates into quinolines under mild
conditions, allowing for the inclusion of acid-sensitive
functionality (such as nitriles and silyl ethers) that would likely
not be tolerated by the more typical, harsh reaction conditions
used to access quinoline derivatives. A one-pot procedure,
eliminating the need to isolate the intermediate Heck products,
was also developed.
Me
N
N
Me
N
Me
4ab
4ac
4ad
: 76%
: 74%
: 91%
Scheme 5. Scope of the photochemical alkene isomerization.
2.4. One-pot Heck reaction/photochemical alkene
isomerization sequence
Finally, we wondered whether we might be able to develop a
one-pot procedure for the sequence, thus obviating the need to
isolate the intermediate Heck product. As both Heck and
photochemical isomerization reactions had been run in toluene,
we hoped that simple irradiation of the crude Heck reaction
mixture would allow for formation of the final quinoline
products. After some optimization we established that this was
the case, and both reactions could be performed in the same
Schlenk tube without an intermediate work-up. The only

5
4. Experimental section
heated-stage microscope equipped with
a
Testo 720
thermometer and are uncorrected. The solvent systems used for
recrystallisation are quoted in parentheses. Photochemical alkene
isomerizations were performed in a 10 mL irradiation vessel
made by Terri Adams at the University of Oxford. The outer
compartment was made of pyrex glass and fitted with inlet and
outlet side-arms. The removable inner glass compartment was
made of fused quartz. A silicone ring placed at the connection of
the two compartments served as a seal and a ring screw cap held
the assembly together, allowing the UV lamp to be held within
the inner compartment. Reactions on were performed with 7–8
mL of solvent to ensure efficient irradiation of the reaction
mixture by the Pen-Ray. Before carrying out photochemical
reactions, the irradiation setup was purged with argon for 30 min.
The argon outlet was then disconnected while maintaining a
moderate argon stream and the reaction solution was added
through the argon outlet with a syringe. The argon outlet was
reattached and the headspace was purged with argon for another
10 min. During photochemical reactions at reduced temperatures,
the vessel was immersed into an ice or cryogenic bath. One-pot
Heck/photochemical alkene isomerizations were performed in a
100 mL Schlenk tube fitted with a 24/40 joint adapter that was
custom-made by Terri Adams at the Department of Chemistry,
University of Oxford. A Teflon ring inside the adapter head
tightly fitted an adjustable-depth pyrex glass inner compartment,
into which the Pen-Ray was placed, providing an airtight seal and
allowing light transmission. The isomerizations in the one-pot
sequence were performed with 45 mL of solvent to ensure
efficient irradiation of the reaction mixture by the Pen-Ray. The
Pen-Ray mercury lamp was purchased from Ultra-Violet
Products, Cambridge, UK (365 nm using a Pen-Ray Light Source
11SC-2.25PB (P/N 90-0019-01)) with a PS-1 power supply.
4.1. General experimental
All solvents and reagents were obtained from Acros, Alfa
Aesar, Fischer Scientific, Fluorochem, Sigma-Aldrich, Strem or
Tokyo Chemical Industry (TCI). All reagents were used as
received or were purified using standard laboratory techniques.
CH2Cl2, tetrahydrofuran (THF), diethyl ether (Et2O) and toluene
(PhMe) were dried over activated 3 molecular sieves for 2 days
and then filtered through an activated alumina purification
column prior to use. Brine refers to a saturated solution of NaCl
in de-ionised H2O. All glassware was flame-dried under vacuum
and reactions performed in an argon atmosphere unless otherwise
stated. All stated temperatures refer to external bath
temperatures. Flash column chromatography was performed with
Merck Kieselgel 60 (0.040–0.063 mm) except where explicitly
stated otherwise. All solvents used for chromatographic
purification were HPLC grade or equivalent and supplied by
Sigma-Aldrich or Fischer Scientific. TLC analyses were
performed on Merck Kieselgel 60 F254 precoated aluminium-
backed plates with layer thickness between 175 and 225 µm.
Product spots were visualised under UV light (λmax = 254 nm)
and/or by staining with a potassium permanganate, vanillin or
phosphomolybdic acid solution. All NMR spectra were recorded
on a Bruker AVIII HD 400 or Bruker AVIII HD 500 instrument
1
with the deuterated solvent acting as internal deuterium lock. H
NMR spectra were recorded at 400 or 500 MHz, 13C NMR
spectra at 101 or 125 MHz with broadband proton decoupling
and 19F NMR spectra at 377 MHz without proton decoupling as
stated. The residual protic solvent signal acted as an internal
1
reference for H NMR and the deuterated solvent carbon signal
acted as an internal reference for 13C NMR (CDCl3: H NMR =
1
7.26 ppm, 13C NMR = 77.16 ppm). 19F NMR spectra were not
externally referenced. Chemical shifts are reported to 0.01 ppm
4.2. General procedure for Heck reactions (GP1)
1
Pd2dba3 (22.9 mg, 25.0 µmol, 5.00 mol%) and tBu3PHBF4
(29.1 mg, 0.100 mmol, 20.0 mol%) were added to a microwave
vial. The vial was flushed with argon and sealed with a crimped
cap. Argon sparged toluene (2.5 mL) and iPr2NEt (0.27 mL, 1.5
mmol, 3.0 equiv) were added and the solution was stirred for 5
min at room temperature. The appropriate bromoaniline 1
(0.5 mmol, 1 equiv) and enone 2 (1.25 mmol, 2.50 equiv) were
dissolved in argon sparged toluene (2.5 mL) and added to the
reaction. The reaction was placed in a pre-heated oil bath at 80 ºC
and stirred for 20 h. The reaction was cooled to room temperature
and filtered through Celite® eluting with EtOAc. The filtrate was
concentrated in vacuo before being purified by flash column
chromatography (SiO2) to afford the title compound.
for H NMR spectra except in cases where two distinguishable
peaks are within 0.01 ppm, in which case the shifts are reported
to 0.001 ppm. Chemical shifts are reported to 0.1 ppm for 13C
NMR spectra except in cases where two distinguishable peaks are
within 0.1 ppm, in which case the shifts are reported to 0.01 ppm.
Coupling constants are quoted to the nearest 0.1 Hz for 1H NMR.
The multiplicity of a signal is reported as such: s–singlet, d–
doublet, t–triplet, q–quartet, quint.–quintet, sext.–sextet, sept.–
septet, oct.–octet, non.–nonet, m–multiplet, br.–broad, app.–
apparent, or combinations thereof. Structural assignments were
made with the aid of DEPT135, COSY, HSQC, HMBC, 1-D nOe
and 2-D NOESY experiments. Fourier-transform infrared (FTIR)
spectra were recorded from evaporated films or neat samples on a
Bruker Tensor 27 spectrometer equipped with a Pike Miracle
Attenuated Total Reflectance (ATR) sampling accessory.
Selected absorption maxima are given in wavenumbers (cm-1).
Electrospray ionisation (ESI) high resolution mass spectrometry
(HMRS) spectra were recorded on a Thermo Exactive orbitrap
spectrometer equipped with a Waters Equity LC system, with a
flow rate of 0.2 mL/min using water:methanol:formic acid
(10:89.9:0.1) as eluent. The system uses a heated electrospray
ionisation (HESI-II) probe and has a resolution of 50,000 FWHM
under conditions for maximum sensitivity, with an accuracy of
better than 5 ppm for 24 h following external calibration on the
day of analysis. The mass reported is that containing the most
abundant isotopes, with each value to 4 decimal places and
within 5 ppm of the calculated mass. The error is calculated with
reference to the values given. UV-visible spectroscopy spectra
4.3. General
procedure
for
photochemical
alkene
isomerization (GP2)
In a 10 mL custom-made irradiation vessel, fitted with an argon
inlet and an outlet to a silicon oil filled bubbler, the appropriate
enone 3 was dissolved in argon-sparged toluene (8 mL) under
argon atmosphere and the reaction cooled to 0 °C. The resulting
colourless solution was irradiated at 365 nm for 17 h. The
reaction was warmed to room temperature and directly
concentrated in vacuo before being purified by flash column
chromatography (SiO2) to afford the title compound.
4.4. General procedure for one-pot Heck
reaction/photochemical alkene isomerization (GP3)
A 100 mL Schlenk tube was fitted with the custom-made
irradiation adapter, with the inner glass compartment adjusted to
the top position. Under a slight positive pressure of argon via the
side-tap, the vessel was sequentially charged with Pd2dba3 (22.9
were recorded on
a
PG instruments T60 UV/VIS
spectrophotometer. All emission spectra were recorded at room
temperature and in steady state mode unless otherwise stated.
Melting points (M.P.) were obtained using a Leica VMTG

6
Tetrahedron
142.3, 134.7, 130.5, 129.0 (2C), 128.3 (2C), 126.1, 34.1 and
8.3 ppm.
mg, 25.0 µmol, 5.00 mol%), tBu3PHBF4 (29.1 mg, 0.100 mmol,
20.0 mol%), the appropriate aryl bromide 1 (0.5 mmol, 1 equiv),
the appropriate enone 2 (1.25 mmol, 2.50 equiv), argon-sparged
toluene (5 mL) and iPr2NEt (0.27 mL, 1.5 mmol, 3.0 equiv). The
vessel was flushed with argon while stirring at room temperature
for 5 min and all joints were sealed with parafilm. The argon tap
was then closed and the reaction stirred at 100 ºC for 20 h. The
reaction was allowed to cool to room temperature and further
argon-sparged toluene (45 mL) was added, the solution was
cooled to 0 ºC and the inner glass custom-made irradiation
adapter was lowered into the solution. The Pen-Ray mercury
lamp was inserted into the inner adapter and the solution was
then irradiated at 365 nm for 20 h. The reaction mixture was
filtered through a plug of Celite® eluting with EtOAc. and
concentrated in vacuo. The filtrate was concentrated in vacuo
before being purified by flash column chromatography (SiO2) to
afford the title compound.
4.5.3 (E)-4-(4-Methoxyphenyl)but-3-en-2-one (2c). NaOH (10%
aq., 5.0 mL) was added dropwise over 30 min to a solution of 4-
methoxybenzaldehyde (1.22 mL, 10.0 mmol) in acetone (7.35
mL, 100 mmol, 10.0 equiv) and H2O (2 mL) at 0 °C. The reaction
was stirred at room temperature for 24 h. HCl (1.0 M, aq.) was
added until pH = 7. The layers were separated and the aqueous
phase was extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and
concetrated in vacuo before being purified by flash column
chromatography (SiO2, pentane:EtOAc, 4:1) to afford the title
compound as a white solid (0.476 g, 27%). Data were consistent
with those previously reported.[23] M.P.: 72–73 ºC (CHCl3). Rf:
0.18 (pentane:EtOAc, 4:1). 1H NMR (400 MHz, CDCl3): δ =
7.50 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 16.2 Hz, 1H), 6.92 (d, J =
8.8 Hz, 2H), 6.61 (d, J = 16.2 Hz, 1H), 3.84 (s, 3H) and 2.36 ppm
(s, 3H). 13C NMR (101 MHz, CDCl3): δ = 198.6, 161.7, 143.4,
130.1 (2C), 127.2, 125.1, 114.6 (2C), 55.5 and 27.6 ppm.
4.5. Experimental procedures: synthesis of starting materials
4.5.1
2-Bromo-4-(2-((triethylsilyl)oxy)ethyl)aniline
(1h).
4.5.4
(E)-4-(Benzo[d][1,3]dioxol-5-yl)but-3-en-2-one
(2d).
Chlorotrimethylsilane (0.44 mL, 2.6 mmol, 1.3 equiv) in CH2Cl2
NaOH (10% aq., 0.29 mL) was added to a solution of piperonal
(1.50 g, 10.0 mmol) in acetone (2.90 mL, 39.4 mmol, 3.94 equiv)
and H2O (0.14 mL) at room temperature. The reaction was stirred
at room temperature for 24 h. HCl (1.0 M, aq.) was added until
pH = 2. The layers were separated and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated
in vacuo before being purified by flash column chromatography
(SiO2, pentane:EtOAc, 4:1) to afford the title compound as a
(4 mL) was added to
a
solution of 2-(4-amino-3-
bromophenyl)ethan-1-ol[21] (0.43 g, 2.0 mmol, 1.0 equiv) and
Et3N (0.56 mL, 4.0 mmol, 2.0 equiv) in CH2Cl2 (16 mL) at –20
°C. The reaction was stirred for 1 h before being warmed to room
temperature. The reaction was diluted with CH2Cl2 and washed
sequentially with NaHCO3 (sat., aq.) and brine. The organic layer
was dried over MgSO4 filtered, and concentrated in vacuo before
being purified by flash column chromatography (SiO2,
pentane:EtOAc, 37:3) to afford the title compound as a colourless
,
white solid (0.81 g, 42%). Data were consistent with those
previously reported.
1
[23]
liquid (0.59 g, 89%). Rf: 0.26 (pentane:EtOAc, 37:3). H NMR
M.P.: 107–110 ºC (CHCl3). Rf: 0.19
1
(400 MHz, CDCl3): δ = 7.27 (s, 1H), 6.94 (dd, J = 8.1, 2.0 Hz,
1H), 6.69 (d, J = 8.1 Hz, 1H), 3.97 (s, 2H), 3.72 (t, J = 7.2 Hz,
2H), 2.70 (t, J = 7.2 Hz, 2H), 0.93 (t, J = 7.9 Hz, 9H) and
0.56 ppm (q, J = 7.9 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ =
142.4, 133.0, 130.6, 129.2, 115.8, 109.4, 64.3, 38.5, 6.9 (3C) and
4.5 ppm (3C). FTIR (thin film) νmax: 3468, 3361, 2953, 2910,
2875, 1620, 1503, 1090, 1036, 1006, 813, 726 and 671 cm–1.
(pentane:EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ = 7.42 (d,
J = 16.1 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.0, 1.6
Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 16.2 Hz, 1H), 6.02
(s, 2H) and 2.35 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ =
198.5, 149.9, 148.6, 143.4, 128.9, 125.4, 125.0, 108.8, 106.6,
101.8 and 27.7 ppm.
4.5.5
(E)-6-Phenylhex-3-en-2-one
(2h).
1-
4.5.2 (E)-1-Phenylpent-1-en-3-one (2b). Cinnamaldehyde (1.70
mL, 13.5 mmol, 1.00 equiv) was added dropwise over 1 h to a
solution of ethylmagnesium bromide (1.0 M in THF, 14.9 mL,
14.9 mmol, 1.10 equiv) in THF (50 mL) at 0 °C. The reaction
was warmed to room temperature and stirred for 12 h before
being quenched by dropwise addition of NH4Cl (sat. aq.). The
layers were separated and the aqueous phase was extracted with
EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. The crude
residue was the dissolved in CH2Cl2 (54 mL) and cooled to 0 °C.
Dess–Martin Periodinane (6.30 g, 14.9 mmol, 1.10 equiv) was
added and the reaction was stirred at 0 °C for 1 h before being
warmed to room temperature and stirred for a further 1 h. The
reaction was diluted with NaHCO3 (sat. aq.) and Na2S2O3 (sat.
aq.) and the layers were separated. The aqueous phase was
extracted with CH2Cl2 and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated
in vacuo before being purified by flash column chromatography
(SiO2, pentane:EtOAc, 19:1) to afford the title compound as a
yellow solid (0.99 g, 45%). Data were consistent with those
previously reported.[22] M.P.: 33–36 ºC (CHCl3). Rf: 0.22
(Triphenylphosphoranylidene)-2-propanone (1.91 g, 6.00 mmol,
1.20 equiv) was added to a solution of 3-phenylproponal (0.66
mL, 5.0 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature and
then stirred until consumption of starting material. The reaction
was directly concentrated in vacuo before being purified by flash
column chromatography (SiO2, pentane:EtOAc, 19:1) to afford
the title compound as a colourless oil (413 mg, 47%). Data were
consistent with those previously reported.[24] Rf: 0.12
1
(pentane:EtOAc, 19:1). H NMR (400 MHz, CDCl3): δ = 7.34–
7.27 (m, 2H), 7.25–7.14 (m, 3H), 6.82 (dt, J = 15.9, 6.8 Hz, 1H),
6.09 (dt, J = 16.0, 1.5 Hz, 1H), 2.83–2.76 (m, 2H), 2.60–2.51 (m,
2H) and 2.23 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ =
198.8, 147.3, 140.8, 131.8, 128.7 (2C), 128.5 (2C), 126.4, 34.5,
34.3 and 27.1 ppm.
4.5.6 (E)-4-Cyclohexylbut-3-en-2-one (2i). NaOH (10% aq., 15
mL) was added dropwise over 30 min to a solution of
cyclohexanecarbaldehyde (1.82 mL, 15.0 mmol) in acetone (11.0
mL, 150 mmol, 10.0 equiv) and H2O (3 mL) at 0 °C. The reaction
was stirred at room temperature for 24 h. HCl (1.0 M, aq.) was
added until pH = 7. The layers were separated and the aqueous
phase was extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo before being purified by flash column
1
(pentane:EtOAc, 19:1). H NMR (400 MHz, CDCl3): δ = 7.66
(dd, J = 16.1 Hz, 1H), 7.56–7.51 (m, 2H), 7.42–7.36 (m, 3H),
6.74 (d, J = 16.2 Hz, 1H), 2.69 (q, J = 7.3 Hz, 2H) and 1.17 ppm
(t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ = 201.0,

7
chromatography (SiO2, pentane:EtOAc, 9:1) to afford the title
compound as a colourless oil (0.94 g, 41%). Data were consistent
with those previously reported.[25] Rf: 0.18 (pentane:EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 6.72 (dd, J = 16.1, 8.1 Hz, 1H),
6.01 (dd, J = 16.2, 1.2 Hz, 1H), 2.23 (s, 3H), 2.19–2.09 (m, 1H),
1.81–1.71 (m, 4H), 1.71–1.64 (m, 1H), 1.36–1.23 (m, 2H) and
1.23–1.09 ppm (m, 3H). 13C NMR (101 MHz, CDCl3): δ = 199.4,
153.6, 128.9, 40.8, 31.9 (2C), 27.0, 26.0 and 25.8 ppm (2C).
[M+H]+ = 270.1290; C17H16FNO requires 270.1289, Δ =
0.37 ppm.
4.6.3 (E)-4-(2-Amino-4-chlorophenyl)-4-phenylbut-3-en-2-one
(3ca). 2-Bromo-5-chloroaniline (103 mg, 0.500 mmol) and (E)-4-
phenylbut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were
subjected to GP1. The reaction was purified by flash column
chromatography (SiO2, pentane:EtOAc, 4:1) to afford the title
compound as
a
yellow oil (89.9 mg, 66%). Rf: 0.11
1
4.5.7 Methyl (E)-2-oxo-4-phenylbut-3-enoate (2j). A solution of
KOH (842 mg, 15.0 mmol, 1.50 equiv) in MeOH (3 mL) was
added dropwise over 30 min to a solution of pyruvic acid (0.695
mL, 10.0 mmol, 1.00 equiv) and benzaldehyde (1.02 mL, 10.0
mmol, 1.00 equiv) in MeOH (0.8 mL) at 0 °C. The reaction was
then stirred at 40 °C for 1 h before being cooled to 0 °C and
stirred overnight. The resulting precipitate was filtered, washed
with MeOH (×2) and Et2O, and dried in vacuo. This solid
(1.29 g) was then added to a solution of acetyl chloride (4.94 mL,
69.5 mmol, 11.5 equiv) in MeOH (34.5 mL) at 0 °C and the
reaction stirred for 30 min before being warmed to room
temperature and stirred for a further 2 h. The reaction was then
stirred at reflux overnight. The reaction was cooled to room
temperature and directly concentrated in vacuo. The residue was
dissolved in water and extracted with CH2Cl2. The organic layer
was washed with NaHCO3 (sat., aq.), H2O and brine, dried over
MgSO4, filtered, and concentrated in vacuo before being purified
by flash column chromatography (SiO2, pentane:EtOAc, 9:1) to
afford the title compound as a yellow solid (435 mg, 22%). Data
were consistent with those previously reported.[26] M.P.: 66–69
(pentane:EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ = 7.44–
7.33 (m, 3H), 7.30–7.23 (m, 2H), 6.96 (d, J = 8.2 Hz, 1H), 6.70
(dd, J = 8.2, 2.1 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.37 (s, 1H),
3.71 (bs, NH2, 2H) and 2.02 ppm (s, 3H). 13C NMR (101 MHz,
CDCl3): δ = 200.8, 151.3, 145.7, 138.3, 135.8, 132.3, 130.1,
129.7, 129.4 (2C), 128.9 (2C), 125.3, 118.4, 116.0 and 30.8 ppm.
FTIR (thin film) νmax: 3478, 3369, 2980, 2980, 1684, 1656, 1619,
1592, 1569, 1488, 1419 and 701 cm–1. HRMS (ESI+): Found
[M+Na]+ = 294.0657; C16H14ClNO requires 294.0656, Δ =
0.34 ppm.
4.6.4 (E)-4-(2-Amino-4-(trifluoromethyl)phenyl)-4-phenylbut-3-
en-2-one (3da). 2-Bromo-5-(trifluoromethyl)-aniline (120 mg,
0.500 mmol) and (E)-4-phenylbut-3-en-2-one (183 mg, 1.25
mmol, 2.50 equiv) were subjected to GP1. The reaction was
purified by flash column chromatography (SiO2, pentane:EtOAc,
4:1) to afford the title compound as a yellow oil (80.2 mg, 52%).
1
Rf: 0.17 (pentane:EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ =
7.44–7.34 (m, 3H), 7.30–7.24 (m, 2H), 7.15 (d, J = 7.9 Hz, 1H),
6.97 (dd, J = 8.0, 1.0 Hz, 1H), 6.86 (d, J = 1.7 Hz, 1H), 6.38 (s,
1H), 3.84 (bs, NH2, 2H) and 2.05 ppm (s, 3H). 13C NMR
(101 MHz, CDCl3): δ = 200.7, 150.6, 144.8, 137.8, 132.0 (q, J =
32.3 Hz), 131.4, 130.6, 129.8, 129.7, 129.2 (2C), 128.9 (2C),
125.4 (q, J = 273.7 Hz), 114.6 (q, J = 3.8 Hz), 112.8 (q, J = 3.9
Hz) and 30.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –63.0 ppm.
FTIR (thin film) νmax: 3480, 3371, 1687, 1662, 1626, 1591, 1436,
1337, 1246, 1168, 1122 and 701 cm–1. HRMS (ESI+): Found
[M+H]+ = 306.1101; C17H14F3NO requires 306.1100, Δ =
0.33 ppm.
1
ºC (CHCl3). Rf: 0.21 (pentane:EtOAc, 9:1). H NMR (400 MHz,
CDCl3): δ = 7.88 (d, J = 16.1 Hz, 1H), 7.68–7.60 (m, 2H), 7.49–
7.40 (m, 3H), 7.37 (d, J = 16.1 Hz, 1H) and 3.94 ppm (s, 3H). 13
C
NMR (101 MHz, CDCl3): δ = 182.5, 162.7, 148.8, 134.1, 131.8,
129.2 (2C), 129.2 (2C), 120.6 and 53.2 ppm.
4.6. Experimental procedures: Synthesis of enones 3
4.6.1 (E)-4-(2-Aminophenyl)-4-phenylbut-3-en-2-one (3aa). 2-
Bromoaniline (86.0 mg, 0.500 mmol) and (E)-4-phenylbut-3-en-
2-one (183 mg, 1.25 mmol, 2.50 equiv) were subjected to GP1.
The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 4:1) to afford the title compound as a
yellow solid (108 mg, 91%). Data were consistent with those
previously reported.[27] M.P.: 84–85 ºC (CHCl3). Rf: 0.12
4.6.5
(E)-4-(5-Acetyl-2-aminophenyl)-4-phenylbut-3-en-2-one
(3ea). 1-(4-Amino-3-bromophenyl)ethan-1-one (107 mg, 0.500
mmol) and (E)-4-phenylbut-3-en-2-one (183 mg, 1.25 mmol,
2.50 equiv) were subjected to GP1. The reaction was purified by
flash column chromatography (SiO2, pentane:Et2O, 1:4) to afford
the title compound as an orange solid (110 mg, 78%). M.P.: 123–
126 ºC (CHCl3). Rf: 0.24 (pentane:Et2O, 1:4). 1H NMR
(400 MHz, CDCl3): δ = 7.79 (dd, J = 8.3, 2.1 Hz, 1H), 7.77 (d, J
= 2.0 Hz, 1H), 7.45–7.35 (m, 3H), 7.31–7.27 (m, 2H), 6.61 (d, J
= 8.3 Hz, 1H), 6.39 (s, 1H), 4.06 (bs, NH2, 2H), 2.51 (s, 3H) and
2.05 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 200.9, 196.4,
150.9, 149.1, 137.8, 132.1, 131.1, 130.6, 129.8, 129.2 (2C), 129.0
(2C), 127.6, 125.7, 115.3, 30.8 and 26.2 ppm. FTIR (thin film)
νmax: 3480, 3358, 3233, 1662, 1622, 1586, 1357, 1286, 1257,
1235 and 700 cm–1. HRMS (ESI+): Found [M+Na]+ = 302.1150;
C18H17NO2 requires 302.1152, Δ = 0.66 ppm.
1
(pentane:EtOAc, 9:1). H NMR (400 MHz, CDCl3): δ = 7.42–
7.34 (m, 3H), 7.31–7.25 (m, 2H), 7.16 (ddd, J = 8.1, 7.3, 1.6 Hz,
1H), 7.04 (dd, J = 7.7, 1.6, 1H), 6.75 (td, J = 7.5, 1.2, 1H), 6.65
(dd, J = 8.1, 1.2, 1H), 6.41 (s, 1H), 3.65 (bs, NH2, 2H) and 2.03
ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 200.9, 152.5,
144.6, 138.8, 131.2, 130.2, 129.9, 129.5, 129.4 (2C), 128.8 (2C),
127.0, 118.4, 116.5 and 30.9 ppm.
4.6.2 (E)-4-(2-Amino-5-fluoro-3-methylphenyl)-4-phenylbut-3-
en-2-one (3ba). 2-Bromo-4-fluoro-6-methylaniline (102 mg,
0.500 mmol) and (E)-4-phenylbut-3-en-2-one (183 mg, 1.25
mmol, 2.50 equiv) were subjected to GP1. The reaction was
purified by flash column chromatography (SiO2, pentane:EtOAc,
7:3) to afford the title compound as a yellow solid (92.6 mg,
68%). M.P.: 111–113 ºC (CHCl3). Rf: 0.17 (pentane:EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 7.44–7.34 (m, 3H), 7.31–7.24
(m, 2H), 6.82 (dd, J = 8.9, 3.0 Hz, 1H), 6.67 (dd, J = 9.1, 3.0 Hz,
1H), 6.38 (s, 1H), 3.50 (bs, NH2, 2H), 2.13 (s, 3H) and 2.04 ppm
(s, 3H). 13C NMR (101 MHz, CDCl3): δ = 200.8, 155.3 (d, J =
236.1 Hz), 151.4 (d, J = 1.7 Hz), 138.7, 138.3, 130.5, 129.6,
129.3 (2C), 128.8 (2C), 127.5 (d, J = 7.5 Hz), 124.9 (d, J =
7.6Hz), 117.8 (d, J = 22.2 Hz), 114.7 (d, J = 22.4 Hz), 30.9 and
18.1 ppm. 19F NMR (376 MHz, CDCl3): δ = –127.7 ppm. FTIR
(thin film) νmax: 3467, 3375, 3056, 2918, 1687, 1657, 1624, 1591,
1475, 1445, 1353, 865 and 707 cm–1. HRMS (ESI+): Found
4.6.6
Methyl
(E)-3-amino-4-(3-oxo-1-phenylbut-1-en-1-
yl)benzoate (3fa). Methyl 3-amino-4-bromobenzoate (115 mg,
0.500 mmol) and (E)-4-phenylbut-3-en-2-one (183 mg, 1.25
mmol, 2.50 equiv) were subjected to GP1. The reaction was
purified by flash column chromatography (SiO2, pentane:EtOAc,
7:3) to afford the title compound as a yellow oil (68.5 mg, 46%).
1
Rf: 0.21 (pentane:EtOAc, 7:3). H NMR (400 MHz, CDCl3): δ =
7.36–7.22 (m, 5H), 7.22–7.16 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H),
6.32 (s, 1H), 3.80 (s, 3H), 3.71 (bs, NH2, 2H) and 1.97 ppm (s,
3H). 13C NMR (101 MHz, CDCl3): δ = 200.7, 167.0, 151.0,
144.6, 137.9, 131.5, 131.1, 131.0, 130.5, 129.7, 129.3 (2C), 128.9
(2C), 119.2, 117.3, 52.3 and 30.9 ppm. FTIR (thin film)
νmax: 3474, 3372, 1718, 1688, 1661, 1623, 1591, 1569, 1438,

8
Tetrahedron
1297, 1237, 765 and 702 cm–1. HRMS (ESI+): Found [M+Na]+ =
318.1096; C18H17NO3 requires 318.1101, Δ = 1.57 ppm.
NH2, 2H) and 2.05 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ
= 201.1, 160.8, 152.4, 144.7, 131.2, 131.2 (2C), 130.7, 130.2,
128.8, 127.3, 118.4, 116.4, 114.1 (2C), 55.5 and 30.9 ppm. FTIR
(thin film) νmax: 3468, 3364, 2360, 2342, 1655, 1605, 1509, 1490,
1453, 1353, 1294, 1250, 1179, 1149, 1029, 840 and 752 cm–1.
HRMS (ESI+): Found [M+H]+ = 268.1339; C17H17NO2 requires
268.1338, Δ = 0.37 ppm.
4.6.7 (E)-4-Amino-3-(3-oxo-1-phenylbut-1-en-1-yl)benzonitrile
(3ga). 4-Amino-3-bromobenzonitrile (98.5 mg, 0.500 mmol) and
(E)-4-phenybut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv)
were subjected to GP1. The reaction was purified by flash
column chromatography (SiO2, pentane:EtOAc, 13:7) to afford
the title compound as a yellow oil (121 mg, 92%). Rf: 0.17
4.6.11 (E)-4-(2-Aminophenyl)-4-(benzo[d][1,3]dioxol-5-yl)but-3-
en-2-one (3ad). (E)- 4-phenylbut-3-en-2-one (86.0 mg, 0.500
mmol) and (E)-4-(benzo[d][1,3]dioxol-5-yl)but-3-en-2-one (238
mg, 1.25 mmol, 2.50 equiv) were subjected to GP1. The reaction
was purified by flash column chromatography (SiO2,
pentane:EtOAc, 7:3) to afford the title compound as a yellow oil
(92.1 mg, 65%). Rf: 0.20 (pentane:EtOAc, 7:3). 1H NMR
(400 MHz, CDCl3): δ = 7.15 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 7.04
(dd, J = 7.6, 1.6 Hz, 1H), 6.85–6.77 (m, 2H), 6.77–6.71 (m, 2H),
6.64 (dd, J = 8.1, 1.1 Hz, 1H), 6.31 (s, 1H), 5.99 (s, 2H), 3.66 (bs,
NH2, 2H) and 2.08 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ
= 200.9, 152.0, 148.9, 148.1, 144.7, 132.5, 131.1, 130.2, 129.3,
127.0, 124.0, 118.4, 116.4, 109.6, 108.5, 101.6 and 30.8 ppm.
FTIR (thin film) νmax: 3469, 3366, 2897, 1656, 1619, 1579, 1487,
1452, 1439, 1356, 1328, 1038, 932 and 753 cm–1. HRMS (ESI+):
Found [M+H]+ = 282.1126; C17H15NO3 requires 282.1125, Δ =
0.33 ppm.
1
(pentane:EtOAc, 13:7). H NMR (400 MHz, CDCl3): δ = 7.46–
7.37 (m, 4H), 7.36 (dd, J = 2.0, 0.4 Hz, 1H), 7.28–7.24 (m, 2H),
6.63 (dd, J = 8.4, 0.4 Hz, 1H), 6.37 (s, 1H), 4.14 (bs, NH2, 2H),
and 2.05 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 200.6,
149.4, 148.3, 137.4, 135.2, 133.8, 130.9, 130.1, 129.20 (2C),
129.15 (2C), 126.6, 119.7, 116.1, 100.6 and 30.9 ppm. FTIR
(thin film) νmax: 3480, 3364, 3229, 2217, 1625, 1603 and
1501 cm–1. HRMS (ESI+): Found [M–H]–
=
261.1028;
C17H14NO2 requires 261.1033, Δ = 1.91 ppm.
4.6.8
(E)-4-(2-Amino-5-(2-((triethylsilyl)oxy)ethyl)phenyl)-4-
phenylbut-3-en-2-one
(3ha).
2-Bromo-4-(2-
((triethylsilyl)oxy)ethyl)aniline (165 mg, 0.500 mmol and (E)-4-
phenylbut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were
subjected to GP1. The reaction was purified by flash column
chromatography (SiO2, pentane:EtOAc, 4:1) to afford the title
compound as a red oil (133 mg, 67%). Rf: 0.18 (pentane:EtOAc,
1
4:1). H NMR (400 MHz, CDCl3): δ = 7.42–7.33 (m, 3H), 7.31–
7.25 (m, 2H), 7.01 (dd, J = 8.1, 2.2 Hz, 1H), 6.90 (d, J = 2.1 Hz,
1H), 6.58 (d, J = 8.1 Hz, 1H), 6.38 (s, 1H), 3.74 (t, J = 7.1 Hz,
2H), 3.52 (bs, NH2, 2H), 2.71 (t, J = 7.1 Hz, 2H), 2.02 (s, 3H),
0.92 (t, J = 7.9 Hz, 9H) and 0.56 ppm (q, J = 7.9 Hz, 6H). 13C
NMR (101 MHz, CDCl3): δ = 201.2, 152.9, 143.0, 139.0, 131.8,
131.1, 130.0, 129.7, 129.6 (2C), 129.3, 128.9 (2C), 127.2, 116.8,
64.7, 38.9, 31.0, 7.1 (3C) and 4.7 ppm (3C). FTIR (thin film)
νmax: 3466, 3368, 2953, 2912, 2875, 1656, 1621, 1589, 1500,
1238, 1094, 1014, 742, 726 and 700 cm–1. HRMS (ESI+): Found
[M+Na]+ = 418.2176; C24H33NO2Si requires 418.2173, Δ =
0.72 ppm.
4.7. Experimental procedures: Synthesis of quinolines 4
4.7.1 2-Methyl-4-phenylquinoline (4aa). From enone 3aa: (E)-4-
(2-Aminophenyl)-4-phenylbut-3-en-2-one (35.5 mg, 0.150
mmol) was subjected to GP2. The reaction was purified by flash
column chromatography (SiO2, pentane:EtOAc, 4:1) to afford the
title compound as a yellow oil (28.7 mg, 87%). One-pot
procedure: 2-Bromoaniline (86.0 mg, 0.500 mmol) and (E)-4-
phenylbut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were
subjected to GP3. The reaction was purified by flash column
chromatography (SiO2, pentane:EtOAc, 5:1) to afford the title
compound as a yellow oil (97.6 mg, 89%). Data were consistent
with those previously reported.[28] Rf: 0.28 (pentane:EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): δ = 8.09 (ddd, J = 8.5, 1.3, 0.6 Hz,
1H), 7.86 (ddd, J = 8.5, 1.5, 0.6 Hz, 1H), 7.69 (ddd, J = 8.4, 6.8,
1.4 Hz, 1H), 7.55–7.46 (m, 5H), 7.43 (ddd, J = 8.2, 6.8, 1.3 Hz,
1H), 7.24 (s, 1H) and 2.78 ppm (s, 3H). 13C NMR (101 MHz,
CDCl3): δ = 158.6, 148.6, 148.5, 138.3, 129.6 (2C), 129.4, 129.1,
128.6 (2C), 128.4, 125.8, 125.8, 125.2, 122.4 and 25.5 ppm.
4.6.9 (E)-1-(2-Aminophenyl)-1-phenylpent-1-en-3-one (3ab). 2-
Bromoaniline (86.0 mg, 0.500 mmol) and (E)-1-phenylpent-1-en-
3-one (200 mg, 1.25 mmol, 2.50 equiv) were subjected to GP1.
The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 4:1) to afford the title compound as a
1
yellow oil (68.1 mg, 54%). Rf: 0.16 (pentane:EtOAc, 4:1). H
NMR (400 MHz, CDCl3): δ = 7.43–7.31 (m, 3H), 7.31–7.23 (m,
2H), 7.15 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.06 (dd, J = 7.7, 1.6
Hz, 1H), 6.75 (td, J = 7.5, 1.2 Hz, 1H), 6.64 (dd, J = 8.0, 1.2 Hz,
1H), 6.42 (s, 1H), 3.63 (s, NH2, 2H), 2.38 (q, J = 7.3 Hz, 2H) and
1.03 ppm (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ =
203.8, 151.8, 144.8, 138.9, 131.2, 130.2, 129.4 (2C), 129.4,
129.0, 128.8 (2C), 127.4, 118.5, 116.6, 37.0 and 8.7 ppm. FTIR
(thin film) νmax: 3370, 2965, 2934, 1686, 1617, 1491, 1452, 1306,
4.7.2 6-Fluoro-2,8-dimethyl-4-phenylquinoline (4ba). (E)-4-(2-
Amino-5-fluoro-3-methylphenyl)-4-phenylbut-3-en-2-one (40.4
mg, 0.150 mmol) was subjected to GP2. The reaction was
purified by flash column chromatography (SiO2, pentane:EtOAc,
97:3) to afford the title compound as a white solid (35.7 mg,
94%). M.P.: 58–61 ºC (CHCl3). Rf: 0.21 (pentane:EtOAc, 97:3).
1H NMR (400 MHz, CDCl3): δ = 7.56–7.44 (m, 5H), 7.34–7.27
(m, 2H), 7.24 (s, 1H), 2.85 (s, 3H) and 2.77 ppm (s, 3H). 13C
NMR (101 MHz, CDCl3): δ = 159.7 (d, J = 244.8 Hz), 156.5,
148.2 (d, J = 5.6 Hz), 144.7, 140.2 (d, J = 9.1 Hz), 138.4, 129.5
(2C), 128.7 (2C), 128.5, 125.8 (d, J = 9.6 Hz), 122.7, 119.3 (d, J
= 25.4 Hz), 106.8 (d, J = 22.5 Hz), 25.6 and 18.7 ppm. 19F NMR
(376 MHz, CDCl3): δ = –115.0 ppm. FTIR (thin film) νmax: 3058,
2924, 2854, 1763, 1622, 1569, 1487, 1124, 863, 764 and 702 cm–
1. HRMS (ESI+): Found [M+H]+ = 252.1183; C17H14FN requires
252.1183, Δ = 0.00 ppm.
1118, 750 and 700 cm–1. HRMS (ESI+): Found [M+H]+
=
252.1383; C17H17NO requires 252.1383, Δ = 0.00 ppm.
4.6.10 (E)-4-(2-Aminophenyl)-4-(4-methoxyphenyl)but-3-en-2-
one (3ac). 2-Bromoaniline (86.0 mg, 0.500 mmol) and (E)-4-(4-
methoxyphenyl)but-3-en-2-one (220 mg, 1.25 mmol, 2.50 equiv)
were subjected to GP1. The reaction was purified by flash
column chromatography (SiO2, pentane:Et2O, 1:1) to afford the
title compound as a yellow oil (87.6 mg, 65%). Rf: 0.11
(pentane:Et2O, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J =
8.7 Hz, 2H), 7.16 (td, J = 7.7, 1.6 Hz, 1H), 7.06 (dd, J = 7.7, 1.6
Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.75 (td, J = 7.5, 1.2 Hz, 1H),
6.64 (dd, J = 8.1, 1.2 Hz, 1H), 6.31 (s, 1H), 3.83 (s, 3H), 3.61 (bs,
4.7.3 7-Chloro-2-methyl-4-phenylquinoline (4ca). (E)-4-(2-
Amino-4-chlorophenyl)-4-phenylbut-3-en-2one (46.6 mg, 0.170

9
mmol) was subjected to GP2. The reaction was purified by flash
column chromatography (SiO2, pentane:EtOAc, 17:3) to afford
the title compound as a yellow solid (35.1 mg, 81%). M.P.: 70–
71 ºC (CHCl3). Rf: 0.18 (pentane:EtOAc, 17:3). 1H NMR
(400 MHz, CDCl3): δ = 8.07 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.9
Hz, 1H), 7.55–7.43 (m, 5H), 7.36 (dd, J = 8.9, 2.2 Hz, 1H), 7.22
(s, 1H) and 2.76 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ =
159.9, 149.0, 148.6, 137.7, 135.3, 129.5 (2C), 128.8 (2C), 128.7,
128.1, 127.2, 126.7, 123.6, 122.4 and 25.5 ppm. FTIR (thin film)
νmax: 3057, 2920, 1593, 1488, 1403, 1180, 1072, 930, 881, 824,
774 and 701 cm–1. HRMS (ESI+): Found [M+H]+ = 254.0733;
C16H12ClN requires 254.0731, Δ = 0.79 ppm.
701 cm–1. HRMS (ESI+): Found [M+H]+
= 278.1175;
C18H15NO2 requires 278.1176, Δ = 0.36 ppm.
4.7.7 2-Methyl-4-phenylquinoline-6-carbonitrile (4ga). From
enone 4ga: (E)-4-Amino-3-(3-oxo-1-phenylbut-1-en-1-
yl)benzonitrile (39.3 mg, 0.150 mmol) was subjected to GP2.
The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 7:3) to afford the title compound as a
white solid (36.1 mg, 98%). One-pot procedure: 4-Amino-3-
bromobenzonitrile (98.5 mg, 0.500 mmol) and (E)-4-phenylbut-
3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were subjected to
GP3. The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 5:1) to afford the title compound as a
white solid (102 mg, 83%). M.P.: 154–157 ºC (CHCl3). Rf: 0.29
4.7.4 2-Methyl-4-phenyl-7-(trifluoromethyl)quinoline (4da). (E)-
4-(2-Amino-4-(trifluoromethyl)phenyl)-4-phenylbut-3-en-2-one
(38.9 mg, 0.127 mmol) was subjected to GP2. The reaction was
purified by flash column chromatography (SiO2, pentane:Et2O,
4:1) to afford the title compound as a yellow oil (29.1 mg, 79%).
1
(pentane:EtOAc, 7:3). H NMR (400 MHz, CDCl3): δ = 8.25 (d,
J = 1.8 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7, 1.9
Hz, 1H), 7.60–7.50 (m, 3H), 7.49–7.43 (m, 2H), 7.36 (s, 1H) and
2.82 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 162.2, 149.6,
149.1, 136.7, 132.5, 130.6, 130.2, 129.5 (2C), 129.2, 129.1 (2C),
1
Rf: 0.18 (pentane:Et2O, 4:1). H NMR (400 MHz, CDCl3): δ =
8.42–8.38 (m, 1H), 7.98 (dt, J = 8.8, 0.9 Hz, 1H), 7.60 (dd, J =
8.8, 1.9 Hz, 1H), 7.57– 7.45 (m, 5H), 7.34 (s, 1H) and 2.80 ppm
(s, 3H). 13C NMR (101 MHz, CDCl3): δ = 160.3, 148.7, 147.6,
137.5, 131.2 (q, J = 32.5 Hz), 129.6 (2C), 128.9 (3C), 127.1,
127.0 (q, J = 4.4 Hz), 126.9, 124.2 (q, J = 272.5 Hz), 124.0,
121.4 (q, J = 3.2 Hz) and 25.5 ppm. 19F NMR (376 MHz,
CDCl3): δ = –62.7 ppm. FTIR (thin film) νmax: 1595, 1373, 1340,
1298, 1185, 1156, 1126, 1065 and 702 cm–1. HRMS (ESI+):
Found [M+H]+ = 288.0993; C17H12F3N requires 288.0995, Δ =
0.69 ppm.
124.9, 123.8, 119.1, 109.5 and 25.8 ppm. FTIR (thin film) νmax:
2921, 2851, 2227, 1726, 1592, 839, 763 and 703 cm–1. HRMS
(ESI+): Found [M+H]+ = 245.1073; C17H12N2 requires 245.1073,
Δ = 0.00 ppm.
4.7.8 2-Methyl-4-phenyl-6-(2-((triethylsilyl)oxy)ethyl)quinoline
(4ha). (E)-4-(2-Amino-5-(2-((triethylsilyl)oxy)ethyl)phenyl)-4-
phenylbut-3-en-2-one (54.0 mg, 0.150 mmol) was subjected to
GP2. The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 17:3) to afford the title compound as an
1
orange oil (53.7 mg, 94%). Rf: 0.20 (pentane:EtOAc, 17:3). H
4.7.5
1-(2-Methyl-4-phenylquinolin-6-yl)ethan-1-one
(4ea).
NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.6 Hz, 1H), 7.67 (d, J
= 1.5 Hz, 1H), 7.56 (dd, J = 8.6, 2.0 Hz, 1H), 7.54–7.45 (m, 5H),
7.19 (s, 1H), 3.82 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H),
2.75 (s, 3H), 0.86 (t, J = 7.9 Hz, 9H) and 0.50 ppm (t, J = 7.9 Hz,
6H). 13C NMR (101 MHz, CDCl3): δ = 157.8, 148.2, 147.4,
138.4, 137.0, 131.3, 129.6 (2C), 128.8, 128.6 (2C), 128.3, 125.2,
125.0, 122.4, 64.0, 39.7, 25.4, 6.8 (3C) and 4.4 ppm (3C). FTIR
(thin film) νmax: 2953, 2875, 1592, 1098, 1015, 834, 745 and
From enone 3ea: (E)-4-(5-Acetyl-2-aminophenyl)-4-phenylbut-
3-en-2-one (41.2 mg, 0.147 mmol) was subjected to GP2. The
reaction was purified by flash column chromatography (SiO2,
pentane:EtOAc, 7:3) to afford the title compound as a white solid
(36.7 mg, 95%). One-pot procedure: 1-(4-Amino-3-
bromophenyl)ethan-1-one (107 mg, 0.500 mmol) and (E)-4-
phenylbut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were
subjected to GP3. The reaction was purified by flash column
chromatography (SiO2, pentane:EtOAc, 5:1) to afford the title
compound as a white solid (100 mg, 76%). M.P.: 133–136 ºC
(CHCl3). Rf: 0.17 (pentane:EtOAc, 7:3). 1H NMR (400 MHz,
CDCl3): δ = 8.49 (d, J = 1.9 Hz, 1H), 8.23 (dd, J = 8.8, 2.0 Hz,
1H), 8.11 (d, J = 8.8 Hz, 1H), 7.58–7.48 (m, 5H), 7.30 (s, 1H),
2.80 (s, 3H) and 2.59 ppm (s, 3H). 13C NMR (101 MHz, CDCl3):
δ = 199.8, 161.3, 150.5, 150.1, 137.5, 134.3, 129.7, 129.6, 129.0
(2C), 128.9 (2C), 128.0, 127.8, 124.4, 123.2, 26.8 and 25.7 ppm.
FTIR (thin film) νmax: 2359, 2342, 1681, 1608, 1592, 1257, 842,
762 and 703 cm–1. HRMS (ESI+): Found [M+H]+ = 262.1226;
C18H15NO requires 262.1226, Δ = 0.00 ppm.
702 cm–1. HRMS (ESI+): Found [M+H]+
=
378.2245;
C24H31NOSi requires 378.2248, Δ = 0.79 ppm.
4.7.9 2-Ethyl-4-phenylquinoline (4ab). (E)-1-(2-Aminophenyl)-1-
phenylpent-1-en-3-one (33.4 mg, 0.132 mmol) was subjected to
GP2. The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 9:1) to afford the title compound as a
1
yellow oil (22.9 mg, 74%). Rf: 0.22 (pentane:EtOAc, 9:1). H
NMR (400 MHz, CDCl3): δ = 8.12 (dt, J = 8.5, 0.8 Hz, 1H), 7.87
(dd, J = 8.5, 1.4 Hz, 1H), 7.69 (ddd, J = 8.4, 8.6, 1.4 Hz, 1H),
7.55–7.46 (m, 5H), 7.43 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.26 (s,
1H), 3.05 (q, J = 7.6 Hz, 2H) and 1.44 ppm (t, J = 7.7 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ = 163.6, 148.8, 148.5, 138.5,
129.7 (2C), 129.3 (2C), 128.6 (2C), 128.4, 125.8, 125.8, 125.4,
121.2, 32.5 and 14.2 ppm. FTIR (thin film) νmax: 3059, 3033,
2967, 2931, 2872, 1593, 1557, 1490, 833, 763 and 701 cm–1.
HRMS (ESI+): Found [M+H]+ = 234.1277; C17H15N requires
234.1277, Δ = 0.00 ppm.
4.7.6 Methyl 2-methyl-4-phenylquinoline-7-carboxylate (4fa).
From enone 3fa: Methyl (E)-3-amino-4-(3-oxo-1-phenylbut-1-
en-1-yl)benzoate (54.6 mg, 0.184 mmol) was subjected to GP2.
The reaction was purified by flash column chromatography
(SiO2, pentane:EtOAc, 3:1) to afford the title compound as a
yellow oil (36.9 mg, 72%). One-pot procedure: Methyl 3-
amino-4-bromobenzoate (115 mg, 0.500 mmol) and (E)-4-
phenylbut-3-en-2-one (183 mg, 1.25 mmol, 2.50 equiv) were
subjected to GP3. The reaction was purified by flash column
chromatography (SiO2, pentane:EtOAc, 5:1) to afford the title
4.7.10 4-(4-Methoxyphenyl)-2-methylquinoline (4ac). (E)-4-(2-
Aminophenyl)-4-(4-methoxyphenyl)but-3-en-2-one (41.4 mg,
0.154 mmol) was subjected to GP2. The reaction was purified by
flash column chromatography (SiO2, pentane:EtOAc, 4:1) to
afford the title compound as a yellow oil (35.3 mg, 91%). Data
were consistent with those previously reported.[29] 1H NMR
(400 MHz, CDCl3): δ = 8.07 (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.90
(ddd, J = 8.4, 1.5, 0.7 Hz, 1H), 7.67 (ddd, J = 8.3, 6.8, 1.5 Hz,
1H), 7.46–7.39 (m, 3H), 7.20 (s, 1H), 7.07–7.01 (m, 2H), 3.88 (s,
3H) and 2.76 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 159.8,
158.6, 148.5, 148.3, 130.8 (2C), 130.5, 129.3, 129.0, 125.8,
125.7, 125.3, 122.3, 114.1 (2C), 55.5 and 25.4 ppm.
compound as
a
yellow oil (109 mg, 78%). Rf: 0.19
1
(pentane:EtOAc, 3:1). H NMR (400 MHz, CDCl3): δ = 8.79 (d,
J = 1.7 Hz, 1H), 8.00 (dd, J = 8.8, 1.4 Hz, 1H), 7.89 (d, J = 8.8
Hz, 1H), 7.56–7.44 (m, 5H), 7.30 (s, 1H), 3.97 (s, 3H) and 2.78
ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 167.0, 159.7,
148.4, 147.9, 137.6, 131.7, 130.7, 129.5 (2C), 128.8 (2C), 128.7,
127.7, 126.1, 125.3, 124.0, 52.5 and 25.5 ppm. FTIR (thin film)
νmax: 2951, 1720, 1593, 1413, 1270, 1235, 1093, 759, 745 and

10
Tetrahedron
4.7.11 4-(Benzo[d][1,3]dioxol-5-yl)-2-methylquinoline (4ad).
(E)-4-(2-Aminophenyl)-4-(benzo[d][1,3]dioxol-5-yl)but-3-en-2-
one (56.9 mg, 0.202 mmol) was subjected to GP2. The reaction
was purified by flash column chromatography (SiO2,
pentane:EtOAc, 7:3) to afford the title compound as an off-white
solid (40.9 mg, 76%). M.P.: 94–97 ºC (CHCl3). Rf: 0.21
(s, 1H), 7.98 (dd, J = 8.5, 1.3 Hz, 1H), 7.79 (ddd, J = 8.4, 6.7, 1.4
Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.58–7.48 (m, 5H)
and 4.09 ppm (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 166.2,
150.1, 148.3, 147.6, 137.6, 131.2, 130.2, 129.7 (2C), 128.9,
128.81 (2C), 128.79, 128.0, 125.9, 121.4 and 53.4 ppm.
1
(pentane:EtOAc, 7:3). H NMR (400 MHz, CDCl3): δ = 8.07 (d,
J = 8.4 Hz, 1H), 7.90 (dd, J = 8.5, 1.4 Hz, 1H), 7.68 (ddd, J =
8.4, 6.8, 1.4 Hz, 1H), 7.44 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.20 (s,
1H), 7.00–6.93 (m, 3H), 6.06 (s, 2H), 2.76 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ = 158.61, 148.57, 148.2, 147.9 (2C), 132.1,
129.4, 129.2, 125.8, 125.7, 125.3, 123.4, 122.3, 110.1, 108.6,
101.5 and 25.5 ppm. FTIR (thin film) νmax: 1593, 1501, 1485,
1439, 1409, 1242, 1225, 1037, 932, 878, 806 and 765 cm–1.
HRMS (ESI+): Found [M+H]+ = 264.1019; C17H13NO2 requires
264.1019, Δ = 0.00 ppm.
Acknowledgments
We are grateful to Cancer Research UK (CR-UK grant
number C38302/A13012), through an Oxford Cancer Research
Center Prize DPhil Studentship (J.C.L.W.), the People
Programme (Marie Curie Actions) of the European Union’s
Seventh Framework Programme (FP7/2007–2013) under REA
grant agreement n8316955 (S.W.) and to the EPSRC Centre for
Doctoral Training in Synthesis for Biology and Medicine
(EP/L015838/1) generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB and Vertex (O.H.).
4.7.12 2-Methyl-4-phenethylquinoline (4ah). 2-Bromoaniline
(86.0 mg, 0.500 mmol) and (E)-6-phenylhex-3-en-2-one
(220 mg, 1.26 mmol, 2.53 equiv) were subjected to GP1. The
reaction was purified by flash column chromatography (SiO2,
pentane:EtOAc, 9:1→7:3) and preperative thin layer
chromatography (SiO2, glass plate, 2000 µm, 20 × 20 cm,
cyclohexane:EtOAc, 8:2) to afford the title compound as a
References and notes
1
yellow oil (100 mg, 81%). Rf: 0.14 (pentane:EtOAc, 4:1). H
1. Heterocycles in Natural Product Synthesis; Majumdar, K. C.;
Chattopaghyay, S. K., Eds.; Wiley-VCH: Weinheim, Germany,
2011.
NMR (400 MHz, CDCl3): δ = 8.07–7.99 (m, 2H), 7.68 (ddd, J =
8.4, 6.9, 1.5 Hz, 1H), 7.51 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.38–
7.28 (m, 2H), 7.28–7.20 (m, 3H), 7.09 (s, 1H), 3.38–3.29 (m,
2H), 3.12–3.01 (m, 2H) and 2.69 ppm (s, 3H). 13C NMR
(101 MHz, CDCl3): δ = 158.8, 148.3, 147.4, 141.3, 129.6, 129.2,
128.7 (2C), 128.5 (2C), 126.5, 125.8, 125.7, 123.3, 121.9, 36.4,
34.3 and 25.5 ppm. FTIR (thin film) νmax: 3026, 2924, 2361,
2. (a) Heterocycles in Drug Discovery; Li, J. J., Ed.; John Wiley and
Sons: Hoboken, USA, 2013. (b) Shang, X.-F.; Morris-Natschke, S.
L.; Liu, Y.-Q.; Guo, X.; Xu, X.-S.; Goto, M.; Li, J.-C.; Yang, G.-
Z.; Lee, K.-H. Biologically active quinolone and quinazoline
alkaloids part I. Med. Res. Rev. 2018, 38, 775–828. (c) Shang, X.-
F.; Morris-Natschke, S. L.; Yang, G.-Z.; Liu, Y.-Q.; Guo, X.; Xu,
X.-S.; Goto, M.; Li, J.-C.; Zhang, J.-Y.; Lee, K.-H. Biologically
active quinolone and quinazoline alkaloids part II. Med. Res. Rev.
2018, 38, 1614–1660.
1601, 749 and 699 cm–1. HRMS (ESI+): Found [M+H]+
=
248.1435; C18H17N requires 248.1434, Δ = 0.40 ppm.
4.7.13 4-Cyclohexyl-2-methylquinoline (4ai). 2-Bromoaniline
(85.2 mg, 0.495 mmol) and (E)-4-Cyclohexyl-3-buten-2-one
(190 mg, 1.25 mmol, 2.53 equiv) were subjected to GP1 with a
modified work up. The crude reaction mixture was diluted in
Et2O and washed with HCl (1.0 M, aq.). K2CO3 was added to the
aqueous phase until pH = 9 and the aqueous phase was then
extracted with CH2Cl2 (×3). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo before
being purified by flash column chromatography (SiO2 15–40 µm,
pentane:EtOAc, 19:1→4:1) to afford the title compound as an
orange oil (43.4 mg, 39%). Data were consistent with those
3. Joule, J. A.; Mills, K. Heterocyclic Chemistry 5th Ed.; Wiley &
Sons: Chichester, 2010.
4. For relevant reviews, see: (a) Bharate, J. B.; Vishwakrma, R. A.;
Bharate, S. B. Metal-free domino one-pot protocols for quinoline
synthesis. RSC Advances 2015, 5, 42020–42053. (b) Prajapati, S.
M.; Patel, K. D.; Vekariya, R. H.; Panchal S. N. Patel, H. D.
Recent advances in the synthesis of quinolones: a review. RSC
Advances 2014, 4, 24463–24476. (c) Barluenga, J.; Rodríguez, F.;
Fañanás, F. J. Recent advances in the Synthesis of Indole and
Quinoline Derivatives through Cascade Reactions. Chem. Asian J.
2009, 4, 1036–1048. For selected recent approaches to quinolines,
see: (d) Mastalir, M; Glatz, M.; Pittenauer, E.; Allmaier, G.;
Kirchner, K. Sustainable Synthesis of Quinolines and Pyrimidines
Catalyzed by Maganese PNP Pincer Complexes. J. Am. Chem.
Soc. 2016, 138, 15543–15546. (e) Liddon, J. T. R.; James, M. J.;
Clarke, A. K.; O'Brien, P.; Taylor, R. J. K. Catalyst-Driven
Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles
and Quinolines from Indonyl Ynones. Chem. Eur. J. 2016, 22,
8777–8780. (f) Su, H.; Bao, M.; Huang, J.; Qiu, L.; Xu, X. Silver-
Catalyzed Carbocyclization of Azide-Tethered Alkynes:
Expeditious Synthesis of Polysubstituted Quinolines. Adv. Synth.
Catal. 2019, 361, 826–831. (g) Jun, J. V.; Petersson, E. J.;
Chenoweth, D. M. Rational Design and Facile Synthesis of a
Highly Tunable Quinoline-Based Fluorescent Small-Molecule
Scaffold for Live Cell Imaging. J. Am. Chem. Soc. 2018, 140,
9486–8493. (h) Wang, C.; Yang, J.; Meng, X.; Sun, Y.; Man, X.;
Li, J.; Sun, F. Manganese(II)-catalyzed dehydrogenative
annulation involving C-C bond formation: highly regioselective
synthesis of quinolines. Dalton Trans. 2019, 48, 4474–4478. (j)
Epton, R. G.; Clarke, A. K.; Taylor, R. J. K.; Unsworth, W. P.;
Lynam, J. M. Synthetic and Mechanistic Studies into the
Rearrangement of Spirocyclic Indolenines into Quinolines. Eur. J.
Org. Chem. 2019, 5563–5571.
1
previously reported.[30] Rf: 0.23 (pentane:EtOAc, 4:1). H NMR
(400 MHz, CDCl3): δ = 8.03 (d, J = 9.0 Hz, 2H), 7.67–7.61 (m,
1H), 7.51–7.45 (m, 1H), 7.16 (s, 1H), 3.37–3.20 (m, 1H), 2.72 (s,
3H), 2.06–1.78 (m, 5H), 1.62–1.43 (m, 4H) and 1.42–1.26 ppm
(m, 1H). 13C NMR (101 MHz, CDCl3): δ = 158.9, 153.5, 148.3,
129.7, 128.9, 125.4, 125.3, 123.0, 118.4, 38.9, 33.7 (2C), 27.1
(2C), 26.5 and 25.6 ppm.
4.7.14 Methyl 4-phenylquinoline-2-carboxylate (4aj). 2-
Bromoaniline (86.5 mg, 0.503 mmol) and methyl (E)-2-oxo-4-
phenylbut-3-enoate (239 mg, 1.26 mmol, 2.50 equiv) were
subjected to GP1 with a modified work up. The crude reaction
mixture was diluted in Et2O and washed with HCl (1.0 M, aq.,
×3). The organic layer was dried over K2CO3 and Na2SO4,
filtered, and concentrated in vacuo before being purified by flash
column chromatography (SiO2 15–40 µm, pentane:EtOAc, 4:1)
to afford the title compound as a pale crystalline solid (68.4 mg,
52%). Data were consistent with those previously reported.[31]
M.P.: 92–99 °C (CH2Cl2). Rf: 0.20 (pentane:EtOAc, 4:1). 1H
NMR (400 MHz, CDCl3): δ = 8.37 (dd, J = 8.6, 1.2 Hz, 1H), 8.16

11
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12
Tetrahedron
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: