Rapid and Efficient Microwave-Assisted Friedl?nder Quinoline Synthesis

Article abstract of DOI:10.1002/open.202000247

A microwave-based methodology facilitates reaction of 2-aminophenylketones with cyclic ketones to form a quinoline scaffold. Syntheses of amido- and amino-linked 17β-hydroxysteroid dehydrogenase type 3 inhibitors with a benzophenone-linked motif were purs

Full text of DOI:10.1002/open.202000247

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Rapid and Efficient Microwave-Assisted Friedländer
Quinoline Synthesis
Helen V. Bailey,[b] Mary F. Mahon,[c] Nigel Vicker,[b] and Barry V. L. Potter*[a, b]
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A microwave-based methodology facilitates reaction of 2-
aminophenylketones with cyclic ketones to form a quinoline
scaffold. Syntheses of amido- and amino-linked 17β-hydroxyste-
roid dehydrogenase type 3 inhibitors with a benzophenone-
linked motif were pursued using 2-aminobenzophenone as
building block. Two amido-linked targets were achieved in
modest yield, but when using microwave-assisted reductive
amination for the amino-linked counterparts an unexpected
product was observed. X-ray crystallography revealed it as a
quinoline derivative, leading to optimisation of a simple and
efficient modification of Friedländer methodology. Using re-
agents and acetic acid catalyst in organic solvent the unassisted
reaction proceeds only over several days and in very poor yield.
However, by employing neat acetic acid as both solvent and
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acid catalyst with microwave irradiation at 160 C quinoline
synthesis is achieved in 5 minutes in excellent yield. This has
advantages over the previously reported high temperatures or
strong acids required, not least given the green credentials of
acetic acid, and examples using diverse ketones illustrate
applicability. Additionally, he unassisted reaction proceeds
effectively at room temperature, albeit much more slowly.
1. Introduction
synthesis can, however, be either acid- or base-catalysed or it
can even proceed without catalysis, although uncatalyzed
reactions require very high temperatures, up to 220 C.[1] In
°
Quinoline derivatives occur in numerous natural products and
pharmaceutical entities, and especially in alkaloids. The arche-
typal example, quinine, was isolated in 1820 from the bark of
the Cinchona tree and used in malaria treatment. Synthesis of
the quinoline ring system is very important to the synthetic
organic chemist and methodology has been widely
discussed,[1,2] with more recent work focusing considerably on
green and clean methodologies.[3] The structural core of quino-
lines can be made by many different methods, one of which is
many cases it has been found that acid catalysis is more
effective than base catalysis.[6] Catalysts used for this reaction
include hydrochloric acid,[6] sulfamic acid,[7] CuCl2,[8] p-toluene-
sulfonic acid,[8] chlorotrimethylsilane[10] and diphenylphosphate
(DPP),[11] amongst others.[1] A comprehensive review on meth-
odology was published in 2009.[12]
The pioneering work by Kappe etal. has been integral in the
undersanding of the scope of microwave (μW)-assisted
reactions.[13] Application of μW-based technologies in organic
synthesis now expedite large scale synthesis, batch processes,
high-throughput library synthesis and flow processes, with
advantages in research and process chemistry and in drug
discovery.[13,14] In line with development of greener technologies
for quinoline synthesis[3] there have also been several μW-
enhanced procedures reported,[6,9–11] demonstrating the advan-
tages that such assisted synthesis can have upon this reaction,
both in speeding it up and improving yields.[15] However, novel
and improved microwave procedures would be highly benefi-
cial.
In studies on the design of enzyme inhibitors as potential
hormone-dependent prostate cancer agents against the type 3
isozyme of enzyme 17β-hydroxysteroid dehydrogenase (17β-
HSD3),[16–18] we designed a new diphenylether-based series of
leads that underwent early stage optimisation from an initial hit
(1 Figure 1) with an IC50 of 700 nM to the related 2 (STX2171),
with potent and selective inhibitory activity and an IC50 of ca
200 nM, and that has been evaluated in vivo.[19] Compound 2
lowered plasma testosterone levels and also inhibited andro-
gen-dependent tumour growth[20] and provided the additional
synthetic versatility of a different hydrophobic headgroup motif
in comparison to the diphenylmethane motif of another potent
in vivo active compound SCH-451659 (STX1383)[20] (Figure 1). To
the Friedländer synthesis, originally published in 1882,[4]
a
versatile and reliable reaction. It is traditionally a reaction in
which an o-aminobenzaldehyde is cyclised by reaction with an
α-methyleneketone in the presence of a base.[5] The Friedländer
[a] Prof. B. V. L. Potter
Medicinal Chemistry & Drug Discovery
Department of Pharmacology
University of Oxford
Mansfield Road
Oxford OX1 3QT (UK)
E-mail: barry.potter@pharm.ox.ac.uk
[b] Dr. H. V. Bailey, Dr. N. Vicker, Prof. B. V. L. Potter
Medicinal Chemistry
Department of Pharmacy & Pharmacology
University of Bath
Claverton Down
Bath BA2 7AY (UK)
[c] Dr. M. F. Mahon
Department of Chemistry
University of Bath
Claverton Down
Bath BA2 7AY (UK)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202000247
© 2020 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
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Figure 1. Diphenylether based inhibitors 1 and 2 and related initial targets in the benzophenone-linked hydrophobic headgroup series: amido-linked 3 and
amino-linked 4. Structure of SCH-451659 (STX1383).
increase structural diversity further we also chose the related 2. Results and Discussion
benzophenone-based analogues as synthetic targets, with both
associated amide and amine linkages, eg 3 and 4 respectively
(Figure 1). Also desirable was exploitation, where possible, of
our methodology for rapid μW-assisted reductive amination of
ketones with anilines, employing sodium triacetoxyborohydride
as reducing agent, a procedure that improves both reaction
rate and efficiency.[21]
The straightforward synthesis of two initial amide-linked targets
in this series is shown in Scheme 1. Only one step was required
from the 2-aminobenzophenone starting material 6 to the final
product
3 and both the unsubstituted 6 and halogen-
substituted 2-amino-5-chloro-2’-fluorobenzophenone 7 were
commercially available. However, a problem was encountered
with reactivity in this series. An amide coupling reaction was
attempted, with 1-acetyl-piperidine-4-carboxylic acid, using 1-
ethyl-3-(dimethylaminopropyl) carbodiimide as activating re-
agent, but this was unsuccessful. Next it was attempted to form
the amide bond using a standard reaction with the correspond-
ing acid chloride. However, the same reactivity problem was
encountered and only starting materials were isolated. A
literature study revealed two articles that used different, and
more forcing, conditions to those attempted. Park etal.[22]
heated such starting materials in dichloromethane (DCM) with
6 eq. pyridine for 6 h and Kettlera etal.[23] used a very similar
method, heating the reaction mixture in toluene for 6 h. These
two sets of conditions were adapted and the desired reaction
was heated in toluene with 6 eq. pyridine for 6 h. This produced
Synthesis of the two initial amide-linked targets 3 and 5
(Scheme 1) including
a disubstituted benzophenone, was
successful in moderate yield and did not require μW-assistance.
However, work on the related amine-based target series,
exemplified by the parent 4 and based upon reaction between
2-aminophenyl ketone 6 and a cyclic ketone 8 (Scheme 2)
utilised our μW-assisted reductive amination strategy, but lead
to an unexpected fused cyclic quinoline by-product 9, as
confirmed by X-ray crystallography. We now report here how
this fortuitous observation was exploited and the reaction
leading to it subsequently optimised to provide an attractive
new variation on the μW-assisted Friedländer quinoline syn-
thesis that was then applied to a series of diverse ketones.
Scheme 1. Synthesis of amide-linked compounds 3 and 5 with a benzophenone-linked headgroup.
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Scheme 2. Synthesis of amine-linked target 4 with a benzophenone head-
group and formation of the alternative product quinoline 9.
the correct products 3 and 5 in both cases with yields of 48%
and 46% respectively.
The synthesis of one of the related amine-linked targets 4 in
this series from 6 and ketone 8 was carried out using a standard
reductive amination method (Scheme 2) but, disappointingly
however, the yield was low (36%). It was hoped that this
reaction could be speeded up and product yield improved and
the reaction was repeated under conditions of the μW-assisted
reductive amination we developed earlier.[21] However, this time
a different major product 9 was obtained, in 60% yield. It was
found that an important difference between the two reactions
was the supply of NaBH(OAc)3 used for the reductive amination.
The reagent used in the second attempt was found to have
degraded, and the alternative product had therefore been
formed in the absence of active reducing agent.
Figure 2. (a) Single crystal X-ray structure of the Friedländer product 9
formed from 2-aminobenzophenone 6 and 1-acetyl-piperidin-4-one 8.
Ellipsoids are represented at 30% probability (b) Hydrogen-bonding in the
gross structure of 9 [symmetry operations: i2 – x, – 1= +y, 1= – z, ii2 – x,
1H and 13C NMR and LCMS data were used to try to identify
the unexpected and crystalline product, but were not con-
clusive. Single crystal X-ray crystallography was therefore
employed to determine the solid-state structure of 9 (Figure 2)
as the substituted quinoline 1-(10-Phenyl-3,4-dihydro-1H-benzo
[b][1,6]-naphthyridin-2-yl)-ethanone (Scheme 2). The X-ray struc-
ture of 9 shows one water molecule hydrogen bonding to the
amide carbonyl in the quinoline and this is repeated in the unit
cell. Thus, fortuitously an interesting modification of the Fried-
länder quinoline synthesis had been uncovered.
2
2
1= +y, 1= – z] Figure 2 (a) shows the quinoline structure 9 identified while
2
2
Figure 2 (b) shows a portion of its crystal packing structure. The included
water molecule acts as a lattice ‘cement’ by hydrogen-bonding to the
quinoline nitrogen (N2) and the carbonyl oxygen (O1) of adjacent lattice
molecules. Propogation of these hydrogen-bonds by virtue of a screw axis
parallel to b axis affords 1-dimensional polymers in the gross array. [H2 C…
ii
i
°
N2 , 2.073(4) Å ; O2-H2CÀ N2, 172(2) ; H2D…O1, 1.958(3) Å ; O2-H2DÀ O1,
ii
1
1
°
174(3) : 2 – x, = +y, = – z].
2
2
Table 1. Effects of time and temperature on the Friedländer synthesis of quinolines from 6 and 10.
Entry
Temperature
(μW heating, C)
Time (min)
Yield (%) [a]
°
1
2
3
4
5
140
140
160
180
200
20
40
20
20
20
70
15
71
78
86
[a]
Isolated yield.
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The Friedländer reaction is generally thought to proceed via
(1 mmol), 10 (2 mmol) in DCE (2 mL) with AcOH (3 mmol) was
heated in an μW vessel and increasing temperature leads to an
increase in product yield of the quinoline 9-Phenyl-1,2,3,4-
tetrahydro-acridine 11. The highest yield was achieved at
1
2
3
4
5
6
7
8
9
the initial formation of a Schiff base, followed by an internal
aldol condensation, although there is still some controversy
about the mechanism.[1] A mechanism for the formation of
either 9 based upon this simplest interpretation or the originally
targeted 4 via a common intermediate is shown in Scheme 3.
The reaction was therefore repeated as previously with μW-
assistance, except without inclusion of the NaBH(OAc)3 and the
yield remained similar at ca 70%. Literature reports of Fried-
länder syntheses generally show high yields, and often better
than the 60–70% yields exhibited so far under our conditions.
2-Aminobenzophenones under thermal or basic conditions do
not react with simple ketones such as cyclohexanone or beta-
keto esters,[24] and acid catalysts such as sulfuric acid,
hydrochloric acid, p-TsOH,[25] and polyphosphoric acids are
more effective than basic catalysts for this reaction.[26,27] This
therefore chimed well with our preliminary observations and
the use of acetic acid in an organic solvent. Many such known
methods, however, require high temperatures, prolonged
reaction times, and sometimes quite drastic reaction conditions
and present work-up difficulties, use stoichiometric or expen-
sive reagents, and for this particular template give less than
satisfactory yields due to side reactions.[12] Development of
more efficient and simple procedures for quinoline syntheses
are needed and we reasoned that there should be considerable
scope and value to attempt optimisation of our simple
procedure. Investigations were therefore targeted at the
discovery of optimal conditions for the reaction using our facile
new μW procedure.
°
°
200 C, but above 200 C there is no longer a significant increase
observed and higher temperatures lead to degradation. Sub-
sequently, in further optimisation of other parameters we
°
showed there was no extra advantage at 200 C and we
°
eventually adopted 160 C as the maximum practical temper-
ature. It was also noted that the optimum reaction time is a
maximum of 20 minutes, as reaction completion was not
reached after 10 minutes and greater reaction times lead to
reduced yields (Entry 2).
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As with the original optimisation of our μW-assisted
reductive amination[21] it was also crucial to investigate an array
of solvents that possess different microwave properties
(Table 2).[14,28] It can be seen that the use of acetonitrile does
not greatly affect product yield, compared to dichloroethane
(DCE) (Entries 1 and 2), whereas use of toluene increases the
yield from 78% to 89% (Entries 1 and 5).
At this point, investigations were undertaken to attempt to
drive the reaction near to completion, by assisting with the
dehydration illustrated in Scheme 3. It was hoped that removal
of water would help to encourage the forward equilibrium and
therefore increase the yield of the reaction. Dehydrated
magnesium sulphate (3 eq.) and 4 Å molecular sieves were
tested, but reduced the isolated yield to 76% and 54%
respectively.
Investigations were also made to see whether the acetic
acid used so far could be successfully substituted for alternative
reagents (Table 3). Results showed that, as expected, acid
catalysis is required for protonation and dehydration, because
without an acid present the yield is reduced to just 17%,
First, a model reaction between 2-aminobenzophenone 6
and cyclohexanone 10 was used to optimise the conditions and
a study into the effects of time and temperature was initiated.
At room temperature alone the reaction proceeds incredibly
slowly, with only an 18% yield of product isolated after 3 days.
The yield was dramatically increased by the use of μW
assistance. The results are shown in Table 1. A solution of 6
Table 2. Effects of solvent on the Friedländer synthesis of quinolines from
6 and 10.
Entry
Solvent
Temperature
(μW heating, C)
Time (min)
Yield
(%) [a]
°
1
2
3
4
5
6
DCE
180
180
140
160
180
180
20
20
20
20
20
10
78
71
78
83
89
72
acetonitrile
Toluene
Toluene
Toluene
Toluene
[a]
Isolated yield.
Table 3. Effects of acid catalyst and solvent on the μW-assisted Friedländer
synthesis of quinolines from 6 and 10.
Entry
Solvent
Acid
Yield (%)[a]
1
2
3
4
5
6
Toluene
Toluene
Toluene
Toluene
Toluene
–
-
17
7
86
84
84
87
Amberlite ICR50 H-form
3eq. p-TSA
1eq. p-TSA
Cat. p-TSA
AcOH as solvent
Scheme 3. Mechanism for the formation of synthetic target 4 and Fried-
länder product 9 from a common Schiff base.
[a]
Isolated yield.
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(Entry 1). Solid phase Amberlite ICR50 H-form was tried but is
also not a suitable alternative reagent, as this reduced the yield
to just 7%, (Entry 2). Conversely, it was found that, as reported
in the literature, p-toluenesulfonic acid (p-TSA) is a very
successful alternative reagent,[9] and even when utilised in
catalytic amounts it leads to excellent yields of 84%, (Entries 3–
5). However, the best condition identified from this study was
the use of neat glacial acetic acid (AcOH) as the solvent, as
operationally this is facile and excellent yields are obtained
(Entry 6).
The use of AcOH both as solvent and acid catalyst is highly
advantageous to this reaction in terms of results and opera-
tional simplicity. The new procedure was therefore simply to
heat 6 (1 mmol) and 10 (2 mmol) in AcOH (2 mL) in a μW tube.
This lead to higher yields and shorter reaction times (Table 4).
The best yields though are obtained with just a 5 or 10 minute
seen to be a greener alternative to that of μW technology,
organic solvents, mineral acids and more complex catalysts etc
in line with current trends.[3] Indeed, when solvents are
evaluated according to low environmental risk acetic acid is
commonly recognized as green. In a recent study of 78
common solvents so classified, acetic acid ranked as 6th best.[29]
Investigations were also carried out to explore the effect, if
any, of reducing the relative amount of ketone used (Table 5).
There was little difference in yields observed when using 1, 1.5
or 2 equivalents of cyclohexanone 10. For this reason, the
amount of ketone used in all subsequent reactions was reduced
to 1.5 equivalents. An excess was used to ensure complete
consumption of the amine. This ratio could be further reduced
if required by a particular application.
Now that conditions had substantially been optimised, this
new procedure was applied to a small range of different
starting ketones and an aldehyde (Table 6). Excellent yields of
quinolines 11–16 were obtained in all cases. The reaction with
2-hexanone showed some degree of regioselectivity as the two
possible products 14a and 14b were obtained in a 1: 1.9 ratio
respectively (Entry 4). In one other case (Entry 6) o-amino-
acetophenone 17[4] was substituted for 6, giving an excellent
yield of quinoline 16 (91%).
1
2
3
4
5
6
7
8
9
10
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°
heating period at 160 C (Entries 2 and 3), with almost optimal
yields obtained. Longer heating periods lead to a small
decrease in isolated yield (Entry 4).
Following the identification of the optimal conditions of
AcOH as solvent and heating in a μW vessel for just 5 minutes
°
at 160 C, further investigations were undertaken to examine
more general applicability. A larger scale reaction was carried
out using 500 mg of 2-aminobenzophenone 6 (2.5 mmol) in the
same volume of AcOH (2 mL), thus more than doubling the
concentration of starting materials. A yield of 95% was
obtained and thus there was no difference due to scale,
showing the process to have high potential for larger scale
reactions, where minimal solvent use is desired.
Application of our new procedure was applied to the
benzophenones in Scheme 1, affording the expected com-
pounds in excellent yields of 68% and 70% respectively
(Scheme 4). However, when 1-acetyl-4-piperidone 8 is used as
the ketone, there is an additional problem concerning the
removal of excess starting ketone. The product and the ketone
co-elute so cannot be separated by flash chromatography.
Although this problem had been reduced by using only 1.5
equivalents of ketone, it was still significant. Luckily, it was
easily solved by stirring the crude product with the electrophile
Thus, with a short reaction time, a cheap solvent and little
excess reagent the attractions of this new procedure are
evident. Interestingly, this system is actually now so efficient
that the reaction proceeds efficiently even at room temperature
(89% yield after 24 h), potentially very useful should μW
technology not be available. While clearly the use of AcOH is
still not perfect in a “green” sense, if reaction rapidity is not an
issue its use as both a solvent and catalyst could certainly be
[30]
scavenger resin PSÀ TsNHNH2 in DCM for 1 hour, the resin
simply removed by filtration and product purified by flash
chromatography. This extra purification may be part of the
reason why these yields are lower than with other compounds
(Table 6) because the overall yield for this step did not actually
show any improvement following the optimisation process. The
new conditions are, however, faster and operationally simpler.
Given the results for biological activity from the parent
diphenyl ether series[19,20] it was likely that these quinoline
based compounds (9 and 18) might be too short for optimal
17β-HSD3 enzyme inhibitory activity, so an extended analogue,
Table 4. Effects of time and temperature on the Friedländer quinoline
synthesis from 6 and 10 when AcOH is used as the solvent.
Entry
Temperature
(μW heating, C)
Time (min)
Yield (%)[a]
°
1
2
3
4
100
160
160
160
5
5
10
20
79
94
94
87
[a]
Isolated yield.
Table 5. Use of differing amounts of ketone on Friedländer quinoline
synthesis from 6 and 10.
Entry
Equivalents of cyclohexanone used
Yield (%)[a]
1
2
3
2
1.5
1
94
92
87
Scheme 4. Synthesis of two quinoline-based products using optimised μW
methodology.
[a]
Isolated yield.
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Table 6. Microwave-assisted Friedländer synthesis of diverse quinolines (using 1.5 equivalents of ketone).
1
2
3
4
5
Entry
1
Starting Material
Ketone
Product
Yield (%)[a]
94
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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2
3
93
99
23b
4
43b
5
6
99
91
[a]
[b]
Isolated yield. Regioisomers obtained, 1:1.9, overall yield 66%.
more akin to SCH-451659 (STX1383) 21 was targeted
(Scheme 5). The initial step between 2-aminobenzophenone 6
and the suitably protected 1-Boc-4-piperidone 19 did not,
however, proceed as envisaged and did not produce the
corresponding Boc-protected intermediate. The reaction lead
instead to the deprotected free amine intermediate 20.
Although not as planned, this made the synthetic route one
step shorter, as the Friedländer synthesis and deprotection
occured in one step and in a good yield of 65%. This does,
however, show that some acid labile groups are not tolerated
by our new Friedländer methodology and other amine
protecting groups may thus prove more suitable. The free
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vanillin, followed by heating. Flash column chromatography was
1
2
3
4
5
6
7
8
9
performed on silica gel (Sorbsil/Matrex C60) or using Argonaut
prepacked columns with a FlashmasterTM. IR spectra were recorded
in DCM solutionin Perkin-Elmer Spectrum RXI FT-IR spectrometer
cells and peak positions are expressed in cmÀ 1. 1H NMR (270 MHz or
400 MHz) and DEPT-edited 13C NMR (68 MHz or 101 MHz) spectra
were recorded with a Jeol Delta 270 or a Varian Mercury VX 400
NMR spectrometer and chemical shifts are reported in parts per
million (ppm). HPLC analyses were performed on
a Waters
Millenium 32 instrument equipped with a Waters 996 PDA detector.
A Waters Radialpack C18 reversed phase column (8×100 mm) was
eluted with the solvent system specified at 1 mL/min. Microwave
irradiation was carried out using a CEM Discover® instrument (CEM
Microwave Discovery Ltd, Buckingham, UK). FAB low and high
resolution mass spectra were recorded at the Mass Spectrometry
Service Centre, University of Bath, using m-nitrobenzyl alcohol
(NBA) as the matrix. ES and APCI low resolution mass spectra were
obtained on a Waters Micromass ZQ. Elemental analyses were
performed by the Microanalysis Service, University of Bath. Melting
points were determined using a Reichert-Jung Thermo Galen Kofler
block and are uncorrected.
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11
12
13
14
15
16
17
18
19
20
21
22
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45
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Scheme 5. Synthesis of an extended quinoline-based analogue using
optimised μW methodology.
amine 20 was then reacted with 1-acetyl-piperidine-4-carbonyl
chloride using standard conditions to give 21. Amine 20 is an
attractive advanced intermediate in its own right for library
construction using parallel synthesis in lead generation/optimi-
sation.
X-Ray Crystallography
Data for 9[34] were obtained at 150K using a Nonius Kappa CCD
diffractometer and MoÀ Kα radiation. Solution and refinement of
the model were effected using the SHELX[35,36] suite of programs via
Olex-2.[37] Refinement was unremarkable and the only point of note
is that the hydrogen atoms, in the included water molecule, were
readily located and refined at a distance of 0.89 Å from O2. For full
details see the Supplementary Information, Table S1.
3. Conclusions
Compounds possessing a quinoline scaffold exhibit a wide
spectrum of pharmacological activities and new methodology
for their synthesis is highly pertinent. In summary, we have
demonstrated here that the quinoline scaffold can be efficiently
and rapidly constructed in excellent yield in only ca 5 min via
the microwave-assisted reaction of a 2-aminophenyl ketone
with cyclic or acyclic ketones using neat acetic acid both as
solvent and catalyst. Using dilute acetic acid in organic solvent
and without microwave assistance the reaction proceeds only
very slowly and in very poor yield. Optimisation of temperature,
solvent, acid catalyst, time and reagent ratio was studied and a
focused range of diverse quinolines was produced to illustrate
reaction versatility. Moreover, should microwave technology
not be readily available the reaction proceeds cleanly and in
high yield alone even at room temperature, albeit over a much
longer timeframe. While highly efficient, the operational
simplicity of this methodology is also greener than a number of
more traditional synthetic approaches. This methodology
should add to the armoury of techniques established for
Friedländer quinoline synthesis[2,3,12,31–33] and find diverse appli-
cations in organic synthesis and for medicinal chemistry.
Crystallographic data for 9 have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
CCDC 2007130. Copies of these data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax(+44) 1223 336033, e-mail: deposit@ccdc.cam.ac.uk
1-Acetyl-piperidine-4-carboxylic acid
(2-benzoyl-phenyl)-amide 3
The above compound was synthesised adapting methodology
reported by Kettlera etal.[23] 1-Acetylpiperidine-4-carbonyl chloride
(173 mg, 0.91 mmol) was dissolved in toluene (5 mL) and this was
added to a solution of 2-aminobenzophenone (150 mg, 0.76 mmol)
and pyridine (0.38 mL, 4.6 mmol) in toluene (15 mL). The resulting
mixture was heated at reflux for 6 h. The toluene was removed in-
vacuo and aqueous HCl solution (1 M) was added. The mixture was
then extracted with DCM, dried (MgSO4), filtered and solution
evaporated to dryness. The crude product was purified by flash
chromatography (0–10% MeOH in DCM), to yield the desired
product as a white solid (129 mg, 48%). Rf 0.44 (10% MeOH in
°
EtOAc), mp: 191–193 C, LCMS: tr =0.94 min (95% MeOH in water),
m/z MÀ H 349.14, HPLC: tr =1.68 min (90% acetonitrile in water),
1
>99%, H NMR (CDCl3, 270 MHz,): δ 1.67–1.87 (2H, m, CH2), 2.01–
2.09 (2H, m, CH2), 2.09 (3H, s, CH3), 2.50–2.61 (1H, m, CH), 2.60–2.75
1
1
(1H, m, = CH2), 3.08–3.17 (1H, m, = CH2), 3.89 (1H, d, J=13.4 Hz,
2
2
49 Experimental SectionMaterials and Methods
50
51
52
53
54
55
56
57
1= CH2), 4.64 (1H, d, J=13.4 Hz, = CH2), 7.09 (1H, td, J=0.97, 7.4 Hz,
1
2
2
ArH), 7.46–7.51 (2H, m, ArH), 7.55–7.63 (3H, m, ArH), 7.67–7.69 (2H,
m, ArH), 8.63–8.66 (1H, m, ArH), 11.10 (1H, s, NH). 13C NMR (CDCl3,
68 MHz): 21.6 (CH3), 28.5, 28.9, 41.1 (CH2), 44.7 (CH), 45.9 (CH2),
121.5, 122.4 (ArCH), 123.1 (ArC), 128.5, 129.9, 132.7, 134.0, 134.7
(ArCH), 138.7, 140.7 (ArC), 167.5, 169.0, 173.2 (CO); HRMS: Calcd for
C21H22N2O3 (M+Na)+373.1526, found (M+Na)+373.1523; Anal.
calcd for C21H22N2O3: C 72.00, H 6.29, N 8.00%, found: C 71.6, H 6.29,
N 8.00%.
All chemicals were purchased from Aldrich Chemical Co. (Gilling-
ham, UK) or Lancaster Synthesis (Morecambe, U.K.). All organic
solvents were supplied by Fisher Scientific (Loughborough, U.K.).
Reactions using anhydrous solvents were carried out under nitro-
gen. Thin layer chromatography (TLC) was performed on precoated
plates (Merck TLC aluminium sheets silica gel 60 F254). Product(s)
and starting material(s) were detected by either viewing under UV
light and/or treating with a suitable staining system, for example
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2.8 mmol/g), this was then stirred at r.t. for 1 h. The resin was
1-Acetyl-piperidine-4-carboxylic acid
[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-amide 5
1
2
3
4
5
6
7
8
9
removed by filtration and flash chromatography isolated the
desired product as a white solid (206 mg, 68%): Rf 0.33 (10% MeOH
in DCM); mp: 163–165 C (from hexane), (lit. 166–167 C[38]); LCMS:
The above compound was synthesised adapting methodology
reported by Kettlera etal.[23] 1-Acetylpiperidine-4-carbonyl chloride
(136 mg, 0.72 mmol) was dissolved in toluene (5 mL) and this was
added to a solution of 2-amino-5-chloro-2’-fluorobenzophenone
(150 mg, 0.6 mmol) in toluene (15 mL). The reaction was heated at
reflux for 2 h. The toluene was removed in vacuo and 1 M HCl was
added, the crude residue was then extracted with DCM, dried
(MgSO4), solution filtered and evaporated to dryness. The crude
product was purified by flash chromatography (0–10% MeOH in
DCM) to yield the desired product as an off-white solid, (112 mg,
°
°
tr =0.95 min (95% MeOH in water); HPLC: tr =1.83 min (90%
1
acetonitrile in water), 99%; H NMR (CDCl3, 270 MHz,): δ 1.95, 2.16
(3H, CH3), 3.29–3.32 (2H, m, CH2), 3.83–3.99 (2H, m, CH2), 4.43, 4.60
(2H, CH2), 7.23–7.28 (2H, m, ArH), 7.38–7.39 (2H, m, ArH), 7.47–7.59
(3H, m, ArH), 7.62–7.70 (1H, m, ArH), 8.04 (1H, t, J=6.6 Hz, ArH); 13C
NMR (CDCl3, 101 MHz): 21.4, 21.9 (CH3), 32.8, 33.9, 39.8, 42.6, 43.8,
46.5 (CH2), 124.0, 124.6 (ArC), 125.9, 126.0, 126.2, 126.3 (ArCH),
126.4, 126.8 (ArC), 128.4, 128.5, 128.6, 128.7, 128.9, 129.0, 129.1,
129.3, 129.5 (ArCH), 135.1, 135.2, 145.1, 146.1, 146.6, 146.9, 155.3,
156.3 (ArC), 169.3, 169.4 (CO); IR: 2800 (m), 1650 (s), 1300 (m), 1030
(m); m/z M+H 303.09; HRMS: Calcd for C20H18N2O (M+H)+
303.1492, found (M+H)+303.1491; Anal. calcd for C20H18N2O (+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
46%). Rf 0.35 (EtOAc), mp: 202–204 C, LCMS: tr =1.07 min (95%
MeOH in water), m/z MÀ H 401.10, HPLC: tr =1.79 min (90%
acetonitrile in water), >99%, 1H NMR (CDCl3, 270 MHz,): δ 1.65–1.90
(2H, m, CH2), 2.02–2.08 (5H, m, CH2 and CH3), 2.51–2.75 (2H, m,
1= mole AcOH): C 75.9, H 6.1, N 8.4%, found: C 76.1, H 6.2, N 9.0%.
2
1
1= CH2 and CH), 3.08–3.18 (1H, m, = CH2), 3.89 (1H, d, J=13.3 Hz,
2
2
This compound was previously synthesised via a different method
1= CH2), 4.63 (1H, d, J=13.3 Hz, 1= CH2), 7.15–7.31 (2H, m, ArH), 7.41–
by Khaldeeva etal.[38]
2
2
7.61 (4H, m, ArH), 8.71 (1H, d, J=8.9 Hz, ArH), 11.35 (1H, br.s, NH).
13C NMR (CDCl3, 68 MHz): 21.5 (CH3), 28.5, 28.9, 41.0 (CH2), 44.7 (CH),
45.8 (CH2), 116.6, 122.5 (ArCH), 123.7 (ArC), 130.3, 133.4, 133.8,
133.9, 135.4 (ArCH), 139.7, 157.7, 161.5 (ArC), 169.0, 173.3, 196.3
(CO); HRMS: Calcd for C21H20ClFN2O3 (M+H)+403.1219, found (M+
H)+403.1218; Anal. calcd for C21H20ClFN2O3: C 62.61, H 5.00, N
6.95%, found: C 62.78, H 5.01, N 6.87%.
9-Phenyl-1,2,3,4-tetrahydro-acridine 11
Following the general procedure for the Friedländer Cyclisation the
desired product was isolated (246 mg, 94%): Rf 0.7 (10% MeOH in
DCM), mp: 137–139 C, (lit. 139–141 C[39]); 1H NMR (CDCl3,
270 MHz,): δ 1.7–1.79 (2H, m, CH2), 1.90–2.01 (2H, m, CH2), 2.59 (2H,
t, J=6.5 Hz, CH2), 3.19 (2H, J=6.4 Hz, CH2), 7.20–7.31 (4H, m, ArH),
7.4–7.65 (4H, m, ArH), 8.00 (1H, d, J=8.2 Hz, ArH); 13C NMR (CDCl3,
68 MHz): 23.0, 23.1, 28.2, 34.4 (CH2), 125.5, 125.9 (ArCH), 127.0 (ArC),
127.8, 128.4, 128.7, 129.2 (ArCH), 137.2, 147.0, 159.2 (ArC); m/z M+
H 400.50; LCMS: tr =4.19 min (50% to 95% MeOH in water at
0.5 mL/min to 1.0 mL/min over 5 min). This compound has been
previously synthesised using a different method, by Shaabani
etal.[39]
°
°
1-[4-(2-Benzoyl-phenylamino)-piperidin-1-yl]-ethanone 4
To a solution of 2-aminobenzophenone (197 mg, 1 mmol) and 1-
acetyl-4-piperidone (282 mg, 2 mmol) in DCE (3 mL) was added
NaBH(OAc)3 (530 mg, 2.5 mmol) and AcOH (0.18 mL). The resulting
solution was stirred at r.t. for 36 h. NaHCO3 was added and the
mixture was extracted with DCM. The crude product was purified
by flash chromatography (0–10% MeOH in EtOAc) to yield the
desired product as a yellow oil (116 mg, 36%). Rf 0.58 (10% MeOH
in EtOAc), LCMS: tr =4.39 min (50% to 95% MeOH in water), m/z (M
+H)+323.14, HPLC: tr =2.03 min (90% acetonitrile in water), 95%,
1H NMR (CDCl3, 270 MHz,): δ 1.48–1.68 (2H, m, CH2), 2.00–2.10 (5H,
m, CH3 and CH2), 3.10–3.34 (2H, m, CH2), 3.67–3.82 (2H, m, CH2),
4.19–4.28 (1H, m, CH2), 6.50–6.56 (1H, m, ArH), 6.78 (1H, d, J=
8.4 Hz, ArH), 7.33–7.59 (7H, m, 6ArH and NH), 8.78 (1H, d, J=7.2 Hz,
ArH). 13C NMR (CDCl3, 68 MHz): 21.6 (CH3), 31.4, 32.2, 39.8, 44.7
(CH2), 48.4 (CH), 111.8, 114.1, 128.2, 129.1, 130.9, 135.1, 136.0
(ArCH), 150.6, 169.0 (CO). HRMS: Calcd for C20H22N2O2 (M+H+Na)+
345.1573, found (M+H+Na)+345.1565.
12-Phenyl-6,7,8,9,10,11-hexahydro-cycloocta[b]quinoline 12
Following the general procedure for the Friedländer Cyclisation the
desired product was isolated as an off-white solid (267 mg, 93%): Rf
°
0.3 (DCM); mp: 120–122 C; HPLC: tr =4.9 min (90% acetonitrile in
water), 98%, H NMR (CDCl3, 270 MHz,): δ 1.30–1.51 (6H, m, CH2),
1
1.90–1.98 (2H, m, CH2), 2.76 (2H, t, J=5.7 Hz, CH2), 3.22 (3H, t, J=
6.2 Hz, CH2), 7.18–7.32 (4H, m, ArH), 7.45–7.51 (3H, m, ArH), 7.55–
7.52 (1H, m, ArH), 8.05 (1H, d, J=7.9 Hz, ArH); 13C NMR (CDCl3,
68 MHz): 25.9, 26.8, 28.2, 31.2, 31.4, 36.5 (CH2), 125.5, 126.2 (ArCH),
127.3 (ArC), 127.7, 128.3, 128.4, 128.6, 129.4 (ArCH), 131.9, 137.7,
146.5, 163.6 (ArC); LCMS: tr =1.78 min (95% MeOH in water), m/z M
+H 288.10; HRMS: Calcd for C21H21N (M+H)+288.1747, found (M+
H)+288.1756; Anal. calcd for C21H21N: C 87.76, H 7.36, N 4.87%,
found: C 87.40, H 7.32, N 4.87%. This compound has been
previously synthesised using a different method, by Bose etal.[40]
General Procedure for the Friedländer Cyclisation
The desired benzophenone (1 mmol) and ketone (2 mmol) were
dissolved in AcOH (2 mL). The resulting solution was subjected to
°
microwave heating for 5 min at 160 C. Saturated NaHCO3 was then
added and the mixture was extracted with DCM, dried (MgSO4),
filtered, the solution concentrated in vacuo and the residue purified
by flash chromatography to yield the desired quinoline product as
detailed below.
9-Phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline 13
Following the general procedure for the Friedländer Cyclisation the
desired product was isolated as an off-white solid (243 mg, 99%): Rf
0.32 (DCM); mp: 132–134 C, (lit. 131–132 C[39]); HPLC: tr =3.2 min
(90% acetonitrile in water), >99%; 1H NMR (CDCl3, 270 MHz): δ
2.10–2.20 (2H, m, CH2), 2.89 (2H, t, J=7.4 Hz, CH2), 3.23 (2H, t, J=
7.7 Hz, CH2), 7.32–7.65 (8H, m, ArH), 8.06–8.08 (1H, m, ArH); 13C NMR
(CDCl3, 68 MHz): 23.6, 30.4, 35.2 (CH2), 126.6, 125.7 (ArCH), 126.3
(ArC), 128.1, 128.4, 128.6, 128.7, 129.4 (ArCH), 133.8, 136.8, 143.0,
147.9, 167.5 (ArC); LCMS: tr =1.5 min (95% MeOH in water), m/z M
+H 245.90; HRMS: Calcd for C18H15N (M+H)+246.1277, found (M+
H)+246.1250. Anal. calcd for C18H15N: C 88.13, H 6.16, N 5.71%,
°
°
1-(10-Phenyl-3,4-dihydro-1H-benzo[b][1,6]
naphthyridin-2-yl)-ethanone 9
Following the general procedure for the Friedländer Cyclisation and
flash chromatography it was found that the product was still
contaminated with the 1-acetyl-4-piperidone starting material. This
was removed by use of PSÀ TsNHNH2. The crude material was
dissolved in DCM (~10 mL/g) and the resin was added (3 eq,
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found: C 87.90, H 6.13, N 5.76%. This compound has been
previously synthesised using a different method, by Shaabani
etal.[39]
142.1, 145.3, 158.5, 171.0 (ArC); m/z M+H 197.71; HRMS: Calcd for
C14H11N (M+H)+198.1277, found (M+H)+198.1271. This compound
was previously synthesised, using a different route, by Wang etal.[43]
1
2
3
4
5
6
2-Butyl-4-phenyl-quinoline 14a and
2-methyl-4-phenyl-3-propyl-quinoline 14b
1-[8-Chloro-10-(2-fluoro-phenyl)-3,4-dihydro-1H-benzo[b][1,6]
naphthyridin-2-yl] ethanone 19
Following the general procedure for the Friedländer Cyclisation the
desired products were synthesised and isolated. Overall yield
(171 mg, 66%), selectivity 1:1.9 (A:B).
Following the general procedure for the Friedländer Cyclisation and
flash chromatography it was found that the product was still
contaminated with 1-acetyl-4-piperidone. This was removed by use
of PSÀ TsNHNH2, the crude material was dissolved in DCM (~10 mL/
g) and the resin was added (3eq, 2.8 mmol/g), this was stirred at r.t.
for 1 h. The resin was removed by filtration and flash chromatog-
raphy isolated the desired product as a white solid (248 mg, 70%):
7
8
9
14a: 2-Butyl-4-phenyl-quinoline was isolated as an off-white oil
(59 mg, 23%): Rf 0.38 (DCM); HPLC: tr =4.75 min (90% acetonitrile in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
water), 93%; H NMR (CDCl3, 270 MHz,): 0.96 (3H, t, J=7.2 Hz, CH3),
1.39–1.52 (2H, m, CH2), 1.79–1.86 (2H, m, CH2), 2.99 (2H, t, J=7.9 Hz,
CH2), 7.39–7.59 (7H, m, ArH), 7.62–7.71 (1H, m, ArH), 8.08–8.11 (1H,
m, ArH); 13C NMR (CDCl3, 68 MHz): 15.0 (CH3), 22.9, 32.4, 39.3 (CH2),
121.7 (ArCH), 125.3 (ArC), 125.7, 125.8, 128.4, 128.6, 129.3, 129.3,
129.6 (ArCH), 138.4, 148.5, 148.6, 148.6, 167.8 (ArC); LCMS: tr =
1.54 min (95% MeOH in water), m/z M+H 261.96; HRMS: Calcd for
C19H19N (M+H)+262.1590, found (M+H)+262.1598. This compound
has been previously synthesised via a different route by Kobayashi
etal.[41]
°
Rf 0.30 (EtOAc); mp: 196–199 C; HPLC: tr =2.07 min (90%
acetonitrile in water), 98%; H NMR (CDCl3, 270 MHz,): δ 2.18 (3H, s,
1
CH3), 3.27–3.33 (2H, m, CH2), 3.81–4.00 (2H, m, CH2), 4.37–4.45 (1H,
1
1
m, = CH2), 4.75 - 4.82 (1H, m, = CH2), 7.19–7.39 (4H, m, ArH), 7.50–
2
2
7.64 (2H, m, ArH), 7.96–8.02 (1H, m, ArH); 13C NMR (CDCl3, 101 MHz):
21.7, 21.8 (CH3), 32.9, 34.0, 39.7, 42.4, 43.7, 46.4 (CH2), 116.7 (d, J=
21.8 Hz, ArCH), 122.0 (ArC), 124.3 (ArCH), 125.1 (d, J=3.7 Hz, ArCH),
126.8 (ArC), 130.5, 130.6, 131.0, 131.5 (ArCH), 132.5, 139.0, 155.7,
157.6, 161.3 (ArC), 169.2, 169.4 (CO); LCMS: tr =1.03 min (95%
MeOH in water), m/z M+H 355.19; HRMS: Calcd for C20H16ClFN2O
(M+Na)+377.0817, found (M+Na)+377.0827; Anal. calcd for
C20H16ClFN2O: C 67.70, H 4.55, N 7.90%, found: C 67.8, H 4.57, N
7.84%.
14b: 2-Methyl-4-phenyl-3-propyl-quinoline was isolated as
a
°
white solid (112 mg, 43%): Rf 0.24 (DCM), mp: 114–116 C; HPLC:
tr =3.87 min (90% acetonitrile in water), >99%; 1H NMR (CDCl3,
270 MHz,): δ 0.81 (3H, t, J=7.4 Hz, CH3CH2), 1.40–1.49 (2H, m, CH2),
2.48–2.54 (2H, m, CH2), 2.80 (3H, s, CH3Ar), 7.20–7.32 (3H, m, ArH),
7.44–7.51 (4H, m, ArH), 7.54–7.61 (1H, m, ArH), 8.03 (1H, dd, J=0.5,
8.4 Hz, ArH); 13C NMR (CDCl3, 68 MHz): 14.5 (CH3), 23.6 (CH2), 23.9
(CH3), 32.5 (CH3), 125.4, 126.2 (ArCH), 127.1 (ArC), 127.6, 128.2,
128.3, 128.4, 129.3 (ArCH), 132.1, 137.4, 145.9, 146.5, 158.6 (ArC);
LCMS: tr =1.41 min (95% MeOH in water), m/z M+H 261.96; HRMS:
Calcd for C19H19N (M+H)+262.1590, found (M+H)+262.1591; Anal.
calcd for C19H19N: C 87.31, H 7.33, N 5.36%, found: C 86.9, H 7.48, N
5.26%.
10-Phenyl-1,2,3,4-tetrahydro-benzo[b][1,6]naphthyridine 20
Following the general procedure for the Friedländer Cyclisation
using 2-aminobenzophenone (197 mg) and 1-Boc-4-piperidone
(300 mg) and subsequent purification (0–10% MeOH in EtOAc, with
5% TEA) the desired product was isolated as a yellow oil (170 mg,
65%): Rf 0.12 (10% MeOH in EtOAc); HPLC: tr =3.20 min (90%
1
acetonitrile in water), 96%; H NMR (CDCl3, 270 MHz,): δ 2.05 (1H,
br.s, NH), 3.21–3.30 (4H, m, 2CH2), 3.84 (2H, s, CH2), 7.20–7.25 (3H,
m, ArH), 7.31–7.33 (2H, m, ArH), 7.45–7.53 (2H, m, ArH), 7.57–7.63
(1H, m, ArH), 8.01 (1H, dd, J=0.8, 9.1 Hz, ArH); 13C NMR (CDCl3,
68 MHz): 34.3, 44.1, 47.5 (CH2), 125.8, 125.9 (ArCH), 126.6, 127.0
(ArC), 128.2, 128.5, 128.8, 129.0 (ArCH), 136.0, 144.9, 146.8, 156.6
(ArC); LCMS: tr =1.70 min (95% MeOH in water), m/z M+H 261.08.
10-Phenyl-3,4-dihydro-1H-pyrano[4,3-b]quinoline 15
Following the general procedure for the Friedländer Cyclisation the
desired product was isolated as a yellow solid (260 mg, 99%): Rf
0.65 (10% MeOH in DCM); mp: 146–148 C (lit. 130 C[42]); HPLC: tr =
2.41 min (90% acetonitrile in water), >99%; 1H NMR (CDCl3,
270 MHz,): δ 1.93 (2H, s, CH2), 2.24 (2H, s, CH2), 4.80 (2H, s, CH2),
7.02–7.12 (2H, m, ArH), 7.21–7.30 (4H, m, ArH), 8.20 (1H, dd, J=
7.7 Hz, ArH); 13C NMR (CDCl3, 68 MHz): 22.1, 24.6 (CH2), 49.8 (CH2),
118.1, 120.7, 122.1, 123.0, 124.0 (ArCH), 125.0 (ArC), 129.2 (ArCH),
129.8 (ArC), 130.1, 130.2, 131.5 (ArCH), 137.7, 153.2, 153.8 (ArC),
169.5, 172.7 (CO); LCMS: tr =1.35 min (95% MeOH in water), m/z
°
°
1-[4-(10-Phenyl-3,4-dihydro-1H-benzo[b][1,6]
naphthyridine-2-carbonyl)-cyclohexyl]-ethanone 21
A solution of 10-phenyl-1,2,3,4-tetrahydro-benzo[b][1,6]naphthyri-
dine (195 mg, 0.38 mmol) in DCM (10 mL) was cooled in an ice bath
and to this was added 1-acetyl-piperidine-4-carbonyl chloride
(282 mg, 0.76 mmol) and TEA (0.46 mL). The resulting solution was
stirred at r.t. for 2 days. NaHCO3 was added and the mixture was
extracted with DCM. The organic portions were washed with 1 M
HCl, dried (MgSO4), filtered and after evaporation in vacuo, the
residue purified using flash chromatography (0–10% MeOH in
EtOAc) to afford the title compound as a cream oil (66 mg, 21%): Rf
0.65 (EtOAc); HPLC: tr =1.65 min (90% acetonitrile in water), 99%;
1H NMR (CDCl3, 400 MHz,): δ (Multiple signals observed due to
MÀ H 262.09; HRMS: Calcd for C18H15NO (M+H)+262.1226, found
3
(M+H)+262.1223. Anal. calcd for C18H15NO: C 82.73, H 5.79, N
5.36%, found: C 82.30, H 5.74, N 5.38%. This compound was
previously synthesised, using a different route, by Kempter etal.[42]
9-Methyl-acridine 16
Following the general procedure for the Friedländer Cyclisation the
desired product was isolated as a yellow oil (180 mg, 91%): Rf 0.14
(DCM), LCMS: tr =1.32 min (95% MeOH in water); HPLC: tr =4.8 min
(90% acetonitrile in water), >99%; 1H NMR (CDCl3, 270 MHz,): δ
1.88–1.92 (4H, m, 2CH2), 2.52 (3H, s, CH3), 2.86 (2H, br.s, CH2), 3.10–
3.12 (2H, m, CH2), 7.41–7.47 (1H, m, ArH), 7.59 (1H, td, J=1.4, 6.9 Hz,
ArH), 7.93 (1H, dd, J=0.81, 8.5 Hz, ArH), 8.00 (1H, d, J=8.5 Hz, ArH),
13C NMR (CDCl3, 68 MHz): 13.8 (CH3), 22.7, 23.2, 27.2, 33.9 (CH2),
123.4, 125.5 (ArCH), 126.9 (ArC), 128.3, 128.5 (ArCH), 128.6, 128.9,
restricted rotation and therefore the presence of rotamers) 1.62–
1.79 (3H, m, CH2 and = CH2), 1.98 (1.3H, s, CH3), 2.02 (1.7H, s, CH3),
1
2
1
1
2.25–2.32 (1H, m, = CH2), 2.66 (1H, t, J=12.0 Hz, = CH2), 2.75–2.84
2
2
1
1
(1H, m, = CH2), 3.04–3.11 (1H, m, = CH2), 3.23–3.31 (2H, m, CH2),
2
2
1
3.67–3.93 (3H, m, CH2 and CH), 4.38–4.63 (3H, m, CH2 and = CH2),
2
7.20 (2H, t, J=9.6 Hz, ArH), 7.30–7.40 (2H, m, ArH), 7.42–7.51 (3H, m,
ArH), 7.60–7.65 (1H, m, ArH), 7.99 (1H, m, ArH); 13C NMR (CDCl3,
101 MHz): 21.4 (CH3), 28.1, 28.3, 28.4, 28.7, 32.5, 34.2 (CH2), 38.4,
ChemistryOpen 2020, 9, 1113–1122
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Full Papers
doi.org/10.1002/open.202000247
ChemistryOpen
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39.0 (CH), 40.5, 40.8, 42.9, 43.1, 45.4, 45.5, 45.7, 45.8 (CH2), 124.2,
124.4 (ArC), 126.0, 126.3, 126.4, 126.7, 128.3, 128.5, 128.7, 128.8,
128.9, 129.0, 129.1, 129.4, 129.6 (ArCH), 135.0, 135.2, 144.7, 146.2,
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Supporting Information
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23
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26
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Full X-ray crystallography table of data for 9.
Acknowledgements
This work was supported by Sterix Ltd., a member of the Ipsen
group. We thank Sterix Ltd for a Research Studentship (to H.V.B.).
We thank Dr W. B. Heaton for useful discussions and advice, Ms A.
Smith for assistance with HPLC and LCMS analysis and the ESPRC
National Mass Spectrometry Service Centre at the University of
Wales, Swansea.
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Keywords: Microwave · optimisation · quinoline · synthesis · X-
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3175.95(10) Å3, Z=8, T=150(2) K, μ(MoKα)=0.087 mmÀ 1
, Dcalc =
1.340 gcmÀ 3
,
52442 reflections measured (8.028 �2θ�55 ), 3638
°
°
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Manuscript received: August 27, 2020
Revised manuscript received: September 1, 2020
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