Modular Three-Component Synthesis of 4-Aminoquinolines via an Imidoylative Sonogashira/Cyclization Cascade

Article abstract of DOI:10.1021/acs.joc.7b02844

We developed a one-pot, two-stage synthetic route to substituted 4-aminoquinolines involving an imidoylative Sonogashira coupling followed by acid-mediated cyclization. This three-component reaction affords pharmaceutically valuable 4-aminoquinolines in a one-pot procedure from readily available starting materials. The reaction tolerates various substituents on the arene as well as the use of secondary and even primary isocyanides. Additionally, the wide tolerance for functionalized isocyanides allows for the one-pot synthesis of various substituted chloroquine analogues as well as other medicinally relevant products.

Full text of DOI:10.1021/acs.joc.7b02844

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Article
Modular Three-Component Synthesis of 4-Aminoquinolines
via an Imidoylative Sonogashira/Cyclization Cascade
Jurriën W. Collet, Kelly Ackermans, Jeffrey Lambregts, Bert U. W. Maes, Romano V. A. Orru, and Eelco Ruijter
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02844 • Publication Date (Web): 20 Dec 2017
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Modular Three-Component Synthesis of 4-Aminoquinolines
via an Imidoylative Sonogashira/Cyclization Cascade
Jurriën W. Collet,† Kelly Ackermans,† Jeffrey Lambregts,† Bert U.W. Maes,‡ Romano V.A. Orru,†,*
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and Eelco Ruijter†,*
†Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines & Sys-
tems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. E-mail:
e.ruijter@vu.nl; r.v.a.orru@vu.nl
http://syborch.com/
‡Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Ant-
werp, Belgium
ABSTRACT:
We developed a one-pot, two-stage synthetic route to substituted 4-aminoquinolines involving an imidoylative So-
nogashira coupling followed by acid-mediated cyclization. This three-component reaction affords pharmaceutically valu-
able 4-aminoquinolines in a one-pot procedure from readily available starting materials. The reaction tolerates various
substituents on the arene as well as the use of secondary and even primary isocyanides. Additionally, the wide tolerance
for functionalized isocyanides allows for the one-pot synthesis of various substituted chloroquine analogues as well as
other medicinally relevant products.
Introduction
AQs have also been reported, as diversely substituted 4-
AQs have been identified as promising antifilarials,11
translocator protein biomarker ligands,12 tuberculosis ATP
synthase inhibitors,13 and as nociceptin receptor antago-
nists.14,15 Additionally, 4-AQs bearing 2-(hetero)aryl func-
tionalities also show promise as non-nucleoside HIV-1
inhibitors.16 Not surprisingly, there is great interest to
efficiently access the 4-AQ core and over the past dec-
ades, several cascade reactions towards these medicinally
valuable scaffolds have been developed (Scheme 1).17-22
For example, 4-AQs can be obtained from the reaction of
ynamides and nitrilium species, resulting from either
arylation of nitriles17 or dehydration of anilides.18 The
Cu(I)-catalyzed cyclization of imidoylacetylenes and sul-
fonyl azides affords 4-AQs as well.19 A carbonylative So-
nogashira reaction of 2-ethynylanilines with in situ ami-
nation at C4 also provides access to 4-AQs.21 Finally, we
recently showed that palladium-catalyzed oxidative isocy-
anide of N-aryl imines by double C-H activation also af-
fords 4-AQs.22 However, these methods rely on rather
specialized starting materials17-20 and/or afford the desired
4-AQs in disappointing yields.18,22 Most diversity-oriented
routes toward 4-AQs rely on the amination of 4-
haloquinolines,23,24 in turn derived from the correspond-
ing 4-quinolones. Such multisubstituted quinolones (2)
are generally difficult to synthesize by traditional conden-
sation methods.25-29 However, quinolones 2 are accessible
via a carbonylative Sonogashira coupling (Scheme 2),
4-Aminoquinolines (4-AQs) have been widely investigat-
ed for their pharmaceutical potential, in particular their
antimalarial properties.1-5 Recently, B ring substituted (in
particular 7-halo) 4-AQs were shown to display enhanced
activities against highly resistant strains of P. falciparum.6
Consequently, this scaffold is still of high interest for the
development of novel antimalarials.7 Additionally, chlo-
roquine and amodiaquine (Fig. 1) have recently been
flagged as leads against Ebola and Marburg viruses.8,9
These known antimalarials also inhibit endosomal Toll-
like receptors (TLRs).10 Recently, other applications of 4-
Figure 1. Examples of medicinally relevant 4-
aminoquinolines.
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Scheme 1. Previous routes to 4-aminoquinolines.
resulting in the formation of isatin diimine 11 (Scheme 3).
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2
3
4
5
6
7
8
If o-bromoaniline is employed, formation of 11 is sup-
pressed to trace amounts, which is known for the synthe-
sis of these isatinimines.35 Surprisingly, these initial exper-
iments revealed that the main product in all cases is the
intermediate imidoylative Sonogashira product 8, with
only trace amounts of the desired cyclization product 9.
Direct formation of 4-AQs 9 from these previously under-
explored ynimines 8 appears to be surprisingly difficult.
Consequently, we focused our attention on the optimiza-
tion of this cycloaromatization. Multiple cyclization con-
ditions were investigated for the formation of aminoquin-
oline 9 from the proposed intermediate ynimine 8. Nei-
ther strong nor weak bases proved effective in facilitating
this cyclization (Table 1, entries 1-2). Weak acids (SiO2,
AcOH) were applied to activate the imine towards cy-
clization, but only afforded cyclization product 9a in trace
quantities (entries 3, 4). However, stronger acids like TFA
(pKa = 0.23), phenylphosphinic acid (pKa = 1.85) and me-
thanesulfonic acid (pKa = -1.9) rapidly afforded 4-amino-
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Scheme 3. Initial Imidoylative Sonogashira studies
towards 4-AQs and side products.
Scheme 2. Carbonylative and imidoylative So-
nogashira coupling to 4-aminoquinolines.
Table 1. Ynimine cyclization optimization.
using organic base to mediate the post-coupling cycliza-
tion (Scheme 2).30-32 To the best of our knowledge, only
one example of isocyanide insertion in a Sonogashira
coupling has been reported, where the product ynimines
are hydrolyzed in situ to the corresponding ynones.33,34
Based on this, we envisioned a direct, one-pot synthesis
of 4-AQs 4 via an imidoylative Sonogashira coupling and
subsequent cycloaromatization (Scheme 2). Such an ap-
proach prevents the need for toxic CO gas, and avoids the
two-step derivatization of quinolones 2.
entrya
Additive (equiv.)
NaOEt (2.0)
yield 9 (%)b
n.r.
1
2
HNEt3 (2.0)
n.r.
3c
4
5
SiO2
trace
trace
100
AcOH (4.0)
HCl in H2O (4.0)
HCl in MeOH (4.0)
HCl in dioxane (4.0)
TFA (4.0)
6
7
96
Results and Discussion
99
Our initial studies showed that such an imidoylative So-
nogashira approach using 5, 6a, and 7a afforded a range
of products as a difficult to analyze mixture under typical
conditions (Scheme 3). Most notably, with temperatures
under 50°C or CuBr loadings approaching stoichiometric
amounts, only the alkyne homocoupling product 10 was
isolated. Additionally, SFC-MS analysis indicated that the
use of o-iodoaniline promotes intramolecular Buchwald-
Hartwig-type reactivity with double isocyanide insertion,
8
9
10
80
PhP(OH)2 (4.0)
85
MeSO3H (4.0)
100
a Conditions: ynimine 8 (0.55 mmol) in DMF (1 mL), additive,
RT, 1 h. b Yield determined by NMR using an internal stand-
ard (1,3,5-trimethoxybenzene). c 0.150 g of SiO2 was used. n.r.
= no reaction, TFA = trifluoroacetic acid.
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attention to the optimization of the imidoylative So-
quinoline 9a, even after short reaction times at ambient
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8
temperature (Table 1, entries 8-10). Interestingly, HCl also
facilitated the cycloaromatization, even when employed
as an aqueous solution. Curiously, acids with non-
nucleophilic conjugate bases also afford aminoquinoline
9a in high to quantitative yield (Table 1, entries 8, 10)
implying either an intermolecular Michael/ Mi-
chael/retro-Michael mechanism,30-32 or a direct intramo-
lecular Michael reaction. Regardless, post-coupling addi-
tion of aqueous hydrochloric acid was selected as the
optimal cyclization condition. While the addition of 1 M
aqueous HCl readily facilitated cycloaromatization of 8 to
9a, we opted for slightly harsher conditions (2 M aq. HCl
(4 mL), 15 min., rt) for the in situ cyclization following the
imidoylative Sonogashira reaction to account for excess
Cs2CO3 as well as any residual starting materials. With the
optimized cyclization protocol in hand, we turned our
nogashira coupling. Using standard conditions (5 mol %
Pd(PPh3)4, 15 mol % CuBr, 2.0 equiv. Cs2CO3, DMSO, 90
°C, 16 h) we obtained the desired 4-AQ 9a in 61% yield
(Table 1, entry 2). When the Cu(I)Br co-catalyst was
omitted, only isatin diimine 11 was obtained (Table 2,
entry 1). Subsequent solvent screening indicated that the
transformation proceeds most efficiently in polar aprotic
solvents, with DMF giving superior results (entries 2-5).
As expected, a heterogeneous palladium catalyst (Pd/C)
did not catalyze the reaction (entry 6). Switching from
Pd(PPh3)4 to an in situ formed Pd0 complex allowed for a
ligand screening (entries 7-10). Interestingly, in addition
to leading to the highest 4-AQ yield, the use of Xantphos
as a ligand completely inhibited the formation of isatin
diimine 11 (Table 1, entry 10). Changing the base from
Cs2CO3 to other inorganic or organic bases (KOtBu,
K2CO3, Et3N, DBU) did not lead to an increase in yield
(entries 11-14).
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Table 2. Optimization of the imidoylative Sonogashira/
cyclization conditions.a
Scheme 4. Alkyne and o-bromoaniline variation.a
entry
1c
Pd source
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd/C
ligand
solvent
DMSO
DMSO
toluene
dioxane
DMF
9a (%)b
--
--
--
2
61
3
--
27
13
4
--
5
--
70
--
6
--
DMF
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
PPh3
DMF
82
--
8
Bu3P
DMF
9
DPEPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
-
DMF
82
91
--
10
11d
12e
13f
14g
15
16
DMF
DMF
DMF
56
--
DMF
DMF
31
DMF
--
XantPhos
DMF
--
a Reaction conditions: 2-bromoaniline (12a, 0.5 mmol, 1
eq), phenylacetylene (6a, 1 mmol, 2 eq), tert-butyl isocya-
nide (7a, 0.625 mmol, 1.25 eq), catalyst (5 mol %), ligand
(monodentate: 15 mol %, bidentate: 10 mol %), CuBr (15
mol %), Cs2CO3 (1 mmol, 2 eq) in solvent (3.0 mL) were
stirred at 100° C for 16-20 h under N2 atmosphere. b Yields
a
Conditions: o-Bromoaniline (12, 1.0 mmol), tert-butyl iso-
1
cyanide (7a, 1.25 mmol), alkyne (6, 2.0 mmol), Pd(OAc)2
determined by H NMR analysis using 2,5-dimethylfuran
as internal standard. c Reaction performed in the absence
of CuBr. d KOtBu (2.0 eq.) employed as base. e K2CO3 (2.0
eq.) employed as base. f Et3N (2.0 eq.) employed as base. g
DBU (2.0 eq.) employed as base.
(0.05 mmol), Xantphos (0.1 mmol), CuBr (0.15 mmol),
b
Cs2CO3 (2.0 mmol) in DMF (8.0 mL). Reaction performed
on 10.0 mmol scale. c Closed vial, 5.0 mmol of 1-hexyne.
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Finally, as anticipated, 9a was not formed when either
described as promising antileishmanials.41 Finally, ethyl 4-
1
2
3
4
5
6
7
8
the palladium source or the ligand was omitted (entries
15, 16).
isocyanopiperidine-1-carboxylate can be used to construct
9ab in 68% yield, providing a handle for further function-
alization of these medicinally valuable scaffolds.
Scheme 5. Isocyanide variation.a
With the optimized reaction conditions in hand, we set
out to explore the compatibility of diversely substituted o-
bromoanilines and terminal alkynes with our three-
component reaction (Scheme 4). The reaction proved
compatible with neutral and moderately electron-
donating substituents (9a,b). The use of halo-substituted
o-bromoanilines did not lead to lower yields (9c-g). Deco-
ration of the o-bromoaniline or the arylalkyne with elec-
tron-donating functionalities afforded the substituted 4-
AQs in high yields (9h-k). However, o-bromoanilines
bearing electron-withdrawing substituents displayed
lower compatibility with the three-component cascade
protocol. When 3-bromo-4-aminobenzoate was used, the
corresponding aminoquinoline 9l was isolated in lower
yield. Similar results were observed for 9m, where the
introduction of an additional distal electron acceptor on
the opposite side of the ynimine renders the alkyne sus-
ceptible to 5-exo-dig cyclization. This cyclization to an
aza-aurone side product most likely accounts for the
diminished yields, as it does not require external acid
activation and can therefore take place during the reac-
tion. Additionally, it is possible that withdrawing electron
density through substituent effects renders ynimines 8
more susceptible to hydrolysis during the cyclization
stage. Gratifyingly, the developed conditions proved to
tolerate aliphatic alkynes as well, as demonstrated by the
isolation of 9n and 9o, with somewhat lower yield for 9n
as a result of the volatility of 1-hexyne.
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Interestingly, this palladium-catalyzed imidoylative So-
nogashira coupling displayed high tolerance with regard
to the isocyanide input (Scheme 5). Secondary isocya-
nides, which are known to undergo double insertion more
readily under palladium catalysis,36,37 proved fully compat-
ible with this protocol (9p-r). Satisfyingly, even primary
isocyanide insertion afforded aminoquinoline 9s in ac-
ceptable yield. The use of bromoanilines and arylalkynes
bearing electron-withdrawing substituents afforded the
corresponding products in lower yields, in accordance
with earlier results (9t-u). Unfortunately, the use of 4-
methoxyphenyl isocyanide did not afford isolable quanti-
ties of the corresponding 4-arylaminoquinoline 9v. We
then investigated the utility of our method in the synthe-
sis of pharmaceutically relevant 4-AQs. The use of readily
accessible N,N-diethyl-4-isocyanopentan-1-amine provid-
ed access to a variety of chloroquine analogues (9w-9y) in
high yields. Similarly, the use of the isocyanide derived
from the known vasoconstrictor octodrine38 afforded 9aa
in good yield. Analogues of this highly fluorescent 2-
naphthyl-4-AQ have been identified as potent immunos-
tumulatory CpG-oligonucleotide antagonists.39,40 Fur-
thermore, the use of 2-bromo-5-fluoroaniline, combined
with N,N-diethyl-4-isocyano-pentan-1-amine and cyclo-
a
Conditions: o-Bromoaniline (1.0 mmol), isocyanide (1.75
mmol), alkyne (2.0 mmol), Pd(OAc)2 (0.05 mmol), Xantphos
(0.1 mmol), CuBr (0.15 mmol), Cs2CO3 (2.0 mmol) in DMF
(8.0 mL).
In conclusion, we have developed an novel one- pot im-
idoylative Sonogashira cross-coupling/acid-mediated
cyclization toward 4-aminoquinolines. The devised meth-
odology is highly compatible with electronically diverse o-
bromoanilines, arylalkynes and aliphatic alkynes, alt-
hough electron-withdrawing substituents on either arene
lead to lower yields. The transformation is compatible
with tertiary, secondary, and even primary aliphatic iso-
cyanides. Additionally, using functionalized alkyl isocya-
nides, this method can be used to directly synthesize 2-
substituted 4-aminoquinolines of high medicinal rele-
vance.
hexylacetylene
furnishes
4-amino-2-cyclohexyl-7-
fluoroquinoline (9z). Structures of this type have been
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with 1 M HCl and sat. NaHCO3, before being dried over
Experimental section
1
anhydrous Na2SO4, filtered, and concentrated in vacuo.
Purification was performed by column chromatography
(gradient, cHex:EtOAc:Et3N 19:1:0.01 – 1:1:0.01, unless stat-
ed otherwise) to afford the pure 4-aminoquinoline deriva-
tive.
General information. Chemicals were purchased from
Sigma Aldrich or Fluorochem and were used without
purification. Solvents were purchased from VWR Chemi-
cals (CH2Cl2), or Sigma Aldrich (toluene, dioxane, DMSO)
and used without purification, unless stated otherwise.
Dry solvents were dried over an Inert PS-MD-5 Solvent
Purification System, equipped with an activated alumina/
2
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9
N-(tert-butyl)-2-phenylquinolin-4-amine (9a) Synthesized
in accordance with general procedure 1. Isolated as a yel-
low solid (0.234 g, 79%); RF = 0.19 (cHex:EtOAc:Et3N
1
copper wire column. H NMR measurements were ac-
1
4:1:0.05); M.p.: 139 °C; H NMR (500.23 MHz, CDCl3): δ
quired on a Bruker Avance 300 (300.13 MHz) or Bruker
Avance 500 (500.23 MHz) spectrometer. 13C NMR meas-
urements were acquired on a Bruker Avance 500 (125.78
MHz) spectrometer. Chemical shifts are reported in ppm
downfield of tetramethylsilane, and are corrected accord-
ing to solvent. Mass analysis was performed using a
Bruker MicrOTOF-Q instrument on a positive ion polari-
ty mode for ESI (Electrospray Ionization). Capillary
charge: 4000V. Melting points were measured using a
Büchi M-565 melting point apparatus. SiO2 column chro-
matography was performed using Merck Silica Gel C60
(particle size 40-60 μm). TLC chromatography was per-
formed on Merck Silica Gel C60 F254 plates (silica coat on
aluminum support). All isolated yields are corrected for
present impurities (if present)
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8.10-8.03 (m, 3H), 7.68 (dd, J = 1.5, 8.5 Hz, 1H), 7.63 (ddd, J
= 1.5, 7.0, 8.5, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.47-7.38 (m,
2H), 7.12 (s, 1H), 5.03 (bs, 1H), 1.60 (s, 9H); 13C NMR
(125.97 MHz, CDCl3): δ 157.9, 148.8, 148.3, 141.2, 130.5,
129.0, 128.8, 128.6, 127.5, 124.3, 118.9, 118.5, 99.1, 51.5, 29.4;
HRMS (ESI): m/z calcd for C19H21N2 [M+H]+ 277.1695,
+
found: 277.1707.
N-(tert-butyl)-7-methyl-2-phenylquinolin-4-amine (9b)
Synthesized in accordance with general procedure 1. Iso-
lated as a yellow solid (0.237 g, 78%); RF = 0.33
1
(cHex:EtOAc:Et3N 4:1:0.05); M.p.: 134 °C; H NMR (500.23
MHz, CDCl3): δ 8.05 (dd, J = 1.5, 7.5 Hz, 2H), 7.85 (s, 1H),
7.57 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.47-7.40
(m, 1H), 7.23 (dd, J = 7.5, 8.5 Hz, 1H), 7.07 (d, J = 1.5 Hz,
1H), 4.99 (bs, 1H), 2.52 (s, 3H), 1.59 (s, 9H); 13C NMR
(125.97 MHz, CDCl3): δ 157.9, 149.0, 148.3, 141.3, 139.0,
General procedure 1 for the synthesis of 4-tert-
butylaminoquinolines from bromoanilines, al-
kynes and tert-butyl isocyanide. A solution of
Pd(OAc)2 (0.011 g, 0.05 mmol) and Xantphos (0.058 g, 0.10
mmol) in dry DMF (8 mL) was stirred for 20 min at RT
under N2 atmosphere, forming a yellow suspension. To
this mixture were added consecutively Cs2CO3 (0.651 g,
2.0 mmol), o-bromoaniline (1.0 mmol), tert-butyl isocya-
nide (0.141 mL, 1.25 mmol), CuBr (0.021 g, 0.15 mmol) and
alkyne (2.0 mmol). The resulting mixture was stirred 90°C
for 16 h. Hereafter, the reaction was allowed to cool to RT,
after which 4 mL 2 M HCl was added and stirred for 15
min. The mixture was diluted with CH2Cl2, filtered over a
pad of diatomaceous earth, and washed with 1 M HCl and
sat. NaHCO3, before being dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Purification was per-
129.7, 128.7, 128.6, 127.5, 126.4, 118.6, 116.4, 98.7, 51.4, 29.4,
+
21.5;
HRMS
(ESI): m/z
calcd
for
C20H23N2
[M+H]+291.1851, found: 291.1854.
N-(tert-butyl)-6-fluoro-2-phenylquinolin-4-amine (9c)
Synthesized in accordance with general procedure 1. Iso-
lated as a light brown solid (0.232 g, 79%); RF = 0.44
(cHex:EtOAc:Et3N 4:1:0.05); M.p.: 163 °C; 1H NMR (500.23
MHz, CDCl3): δ 8.14-8.06 (m, 3H), 7.54 (t, J = 7.5 Hz, 2H),
7.50-7.44 (m, 1H), 7.48-7.37 (m, 1H), 7.36 (dd, J = 2.5, 10.0
Hz, 1H), 7.17 (s, 1H), 4.79 (bs, 1H), 1.57 (s, 9H); 13C NMR
(125.97 MHz, CDCl3): δ 159.5 (d, J = 245.0 Hz), 157.3 (d, J =
2.5 Hz), 147.9 (d, J = 4.5 Hz), 145.8, 140.9, 132.8 (d, J = 8.5
Hz), 128.8, 128.6, 127.4, 118.9 (d, J = 8.0 Hz), 118.6 (d, J =
24.5 Hz), 103.3 (d, J = 23.0 Hz), 99.4, 51.6, 29.3; HRMS
(ESI): m/z calcd for C19H20N2F+ [M+H]+ 295.1601, found:
295.1604.
formed
by
column
chromatography
(gradient,
cHex:EtOAc:Et3N 19:1:0.01 – 1:1:0.01, unless stated other-
wise) to afford the pure 4-aminoquinoline derivative.
N-(tert-butyl)-6-fluoro-2-(p-tolyl)quinolin-4-amine (9d)
Synthesized in accordance with general procedure 1. Iso-
lated as a light brown solid (0.241 g, 78%); RF = 0.43
General procedure 2 for the synthesis of 4-
aminoquinolines from bromoanilines, alkynes
and isocyanides. A solution of Pd(OAc)2 (0.011 g, 0.05
mmol) and Xantphos (0.058 g, 0.10 mmol) in dry DMF (8
mL) was stirred for 20 min at RT under N2 atmosphere,
forming a yellow suspension. To this mixture were added
consecutively Cs2CO3 (0.651 g, 2.0 mmol), o-bromoaniline
(1.0 mmol), isocyanide (1.75 mmol), CuBr (0.021 g, 0.15
mmol) and alkyne (2.0 mmol). The resulting mixture was
stirred 90°C for 16 h. Hereafter, the reaction was allowed
to cool to RT, after which 4 mL 2 M HCl was added and
stirred for 15 min. The mixture was diluted with CH2Cl2,
filtered over a pad of diatomaceous earth, and washed
1
(cHex:EtOAc:Et3N 4:1:0.05); M.p.: 155 °C; H NMR (500.23
MHz, CDCl3): δ 8.04 (dd, J = 5.5, 9.0 Hz, 1H), 7.95 (d, J =
8.0 Hz, 2H), 7.42-7.36 (m, 1H), 7.34-7.27 (m, 3H), 7.12 (s,
1H), 4.74 (bs, 1H), 2.43 (s, 3H), 1.59 (s, 9H); 13C NMR
(125.97 MHz, CDCl3): δ 159.5 (d, J = 245.0 Hz), 157.3 (d, J =
2.5 Hz), 147.8 (d, J = 5.0 Hz), 145.8, 138.8, 138.0, 132.7 (d, J =
8.5 Hz), 129.4, 127.3, 118.9 (d, J = 8.0 Hz), 118.5 (d, J = 25.0
Hz), 103.3 (d, J = 23.0 Hz), 99.3, 51.5, 29.3, 21.3; HRMS
(ESI): m/z calcd for C20H22N2F+ [M+H]+ 309.1757, found:
309.1769.
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51.5, 29.4; HRMS (ESI): m/z calcd for C20H23N2O+ [M+H]+
307.1800, found: 307.1788.
N-(tert-butyl)-6-chloro-8-fluoro-2-(p-tolyl)quinolin-4-
amine (9e) Synthesized in accordance with general pro-
cedure 1. Isolated as a yellow solid (0.253 g, 78%); RF =
0.69 (cHex:EtOAc:Et3N 4:1:0.01); M.p.: 166-167 °C; 1H NMR
(500.23 MHz, CDCl3): δ 7.98 (dd, J = 8.0, 2.0 Hz, 1H), 7.42
(s, 1H), 7.34-7.28 (m, 3H), 7.17 (s, 1H), 4.86 (s, 0H), 2.42 (s,
3H), 1.59 (s, 9H); 13C NMR (125.97 MHz, CDCl3): δ 159.8,
157.8 (d, J = 18.5 Hz), 147.3 (d, J = 3.5 Hz), 138.4 (d, J = 235.5
Hz), 138.2 (d, J = 11.0 Hz), 129.4, 128.5 (d, J = 11.0 Hz),
127.37, 120.6 (d, J = 3.5 Hz), 114.7 (d, J = 23.0 Hz), 114.4 (d, J
= 4.5 Hz), 100.1, 51.8, 29.3, 21.4; HRMS (ESI): m/z calcd for
C20H21N2ClF+ [M+H]+ 343.1368, found: 343.1376.
1
2
3
4
5
6
7
8
N-(tert-butyl)-2-(3,4,5-trimethoxyphenyl)quinolin-4-
amine (9j) Synthesized in accordance with general pro-
cedure 1. Isolated as a yellow solid (0.319 g, 87%); RF = 0.10
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 67-69 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.06 (d, J = 8.5 Hz, 1H), 7.68 (d, J
= 8.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz,
1H), 7.26 (s, 2H), 7.03 (s, 1H), 5.06 (bs, 1H), 3.99 (s, 6H),
13
9
3.90 (s, 3H), 1.59 (s, 9H); C NMR (125.97 MHz, CDCl3): δ
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
58
59
60
157.8, 153.3, 184.6, 148.6, 148.4, 138.9, 130.3, 129.1, 124.4,
118.9, 118.4, 104.9, 99.1, 60.3, 56.2, 51.5, 29.4; HRMS
(ESI): m/z calcd for C22H27N2O3+ [M+H]+ 367.2010, found:
367.2026.
N-(tert-butyl)-7-chloro-2-(3-chlorophenyl)quinolin-4-
amine (9f) Synthesized in accordance with general pro-
cedure 1. Isolated as a yellow solid (0.231 g, 67%); RF = 0.58
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 51-54 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.08-7.98 (m, 2H), 7.89 (d, J = 6.5
Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.47-7.39 (m, 2H), 7.34 (d,
N-(tert-butyl)-7-chloro-2-(3,4,5-trimethoxyphenyl)
quinolin-4-amine (9k) Synthesized in accordance with
general procedure 1. Isolated as a yellow solid (0.328 g,
82%); RF = 0.28 (cHex:EtOAc:Et3N 4:1:0.01); M.p.: 68-70 °C;
1H NMR (500.23 MHz, CDCl3): δ 8.03 (s, 1H), 7.60 (dd, J =
2.0, 9.0 Hz, 1H), 7.33 (dt, J = 2.0, 9.0 Hz, 1H), 7.25 (d, J = 1.5
Hz, 2H), 7.02 (d, J = 1.5 Hz, 1H), 5.00 (bs, 1H), 3.98 (s, 6H),
13
J = 9.0 Hz, 1H), 7.04 (s, 1H), 5.03 (bs, 1H), 1.59 (s, 9H); C
NMR (125.97 MHz, CDCl3): δ 157.3, 149.5, 148.6, 142.5,
135.0, 134.7, 129.9, 129.3, 129.0, 127.6, 125.5, 125.2, 120.5,
117.0, 98.9, 51.7, 29.3; HRMS (ESI): m/z calcd for
C19H19N2Cl2+ [M+H]+ 345.0917, found: 345.0925.
13
3.91 (s, 3H), 1.59 (s, 9H); C NMR (125.97 MHz, CDCl3): δ
158.7, 153.3, 149.5, 148.4, 139.1, 136.6, 134.9, 129.2, 124.9,
120.5, 116.9, 104.8, 99.2, 60.9, 56.3, 51.7, 29.3; HRMS
(ESI): m/z calcd for C22H26N2O3Cl+ [M+H]+ 401.1621,
found: 401.1634.
N-(tert-butyl)-2-(4-fluorophenyl)quinolin-4-amine (9g)
Synthesized in accordance with general procedure 1. Iso-
lated as a yellow solid (0.252 g, 77%); RF = 0.33
(cHex:EtOAc:Et3N 4:1:0.05); M.p.: 138 °C; 1H NMR (500.23
MHz, CDCl3): δ 8.09-8.01 (m, 3H), 7.68 (d, J = 8.5 Hz, 1H),
7.67-7.60 (m, 1H), 7.44-7.37 (m, 1H), 7.19 (t, J = 8.5 Hz,
2H), 7.06 (s, 1H), 5.05 (bs, 1H), 1.60 (s, 9H); 13C NMR
(125.97 MHz, CDCl3): δ 163.4 (d, J = 248.0 Hz), 156.8, 148.8,
148.4, 137.3 (d, J = 3.0 Hz), 130.4, 129.2 (d, J = 8.5 Hz), 129.1,
124.4, 118.9, 118.4, 115.5 (d, J = 21.5 Hz), 98.7; HRMS
(ESI): m/z calcd for C19H20N2F+ [M+H]+ 295.1601, found:
295.1601.
Methyl
4-(tert-butylamino)-2-phenylquinoline-6-
carboxylate (9l) Synthesized in accordance with general
procedure 1. Isolated as a yellow solid (0.147 g, 44%); RF =
0.38 (cHex:EtOAc:Et3N 4:1:0.01); M.p.: 131-134 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.49 (s, 1H), 8.19 (dd, J = 2.0, 8.5
Hz, 1H), 8.11-8.02 (m, 3H), 7.56-7.49 (m, 2H), 7.49-7.45 (m,
1H), 7.15 (s, 1H), 5.27 (bs, 1H), 3.99 (s, 3H), 1.62 (s, 9H); 13C
NMR (125.97 MHz, CDCl3): δ 167.0, 159.8, 151.3, 149.4,
140.7, 130.5, 129.3, 128.7, 128.6, 127.6, 125.2, 122.5, 117.7, 99.5,
+
52.3, 51.9, 29.3; HRMS (ESI): m/z calcd for C21H23N2O2
N-(tert-butyl)-7-fluoro-2-(4-methoxyphenyl)quinolin-4-
amine (9h) Synthesized in accordance with general pro-
cedure 1. Isolated as a yellow solid (0.257 g, 79%); RF =
0.38 (cHex:EtOAc:Et3N 4:1:0.01); M.p.: 47-49 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.11-7.99 (m, 2H), 7.78-7.57 (m,
2H), 7.13 (t, J = 8.5 Hz, 1H), 7.08-6.93 (m, 3H), 4.97 (bs,
1H), 3.88 (s, 3H), 1.59 (s, 9H); 13C NMR (125.97 MHz,
CDCl3): δ 163.0 (d, J = 248.0), 160.5, 158.5, 150.3 (d, J = 12
Hz), 148.4, 133.3, 128.8, 121.1 (d, J = 10.0 Hz), 114.0, 113.7 (d, J
= 19.5), 113.6 (d, J = 25.0 Hz), 98.3, 55.4, 51.6, 29.4); HRMS
(ESI): m/z calcd for C20H22N2FO+ [M+H]+ 325.1706, found:
325.1723.
[M+H]+ 335.1749, found: 335.1759.
4-(4-(tert-butylamino)quinolin-2-yl)benzonitrile (9m)
Synthesized in accordance with general procedure 1. Iso-
lated as a yellow solid (0.090 g, 31%); RF = 0.33
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 79-81 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.18 (d, J = 8.5 Hz, 2H), 8.04 (dd, J
= 1.5, 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 1.5,
8.5 Hz, 1H), 7.66 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H), 7.45 (ddd, J
= 1.5, 7.0, 8.5 Hz, 1H), 7.09 (s, 1H), 5.13 (bs, 1H), 1.61 (s, 9H);
13C NMR (125.97 MHz, CDCl3): δ 155.6, 148.7, 145.4, 132.5,
130.6, 129.4, 128.1, 125.1, 119.0, 118.9, 118.6, 112.2, 98.7, 51.7,
29.3; HRMS (ESI): m/z calcd for C20H20N3+ [M+H]+
302.1648, found: 302.1656.
N-(tert-butyl)-7-methoxy-2-phenylquinolin-4-amine (9i)
Synthesized in accordance with general procedure 1. Iso-
lated as a bright yellow solid (0.236 g, 77%); RF = 0.29
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 56-61 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.06 (m, 2H), 7.57 (d, J = 9.0, 1H),
7.54-7.47 (m, 2H), 7.46-7.41 (m, 2H), 7.04 (dd, J = 2.5, 9.0
Hz, 1H), 7.02 s, 1H), 4.96 (bs, 1H), 3.94 (s, 3H), 1.58 (s, 9H);
13C NMR (125.97 MHz, CDCl3): δ 160.2, 158.4, 150.7, 148.5,
141.3, 128.7, 128.6, 127.4, 120.2, 116.7, 112.9, 108.6, 98.2, 55.4,
N-(tert-butyl)-2-butylquinolin-4-amine (9n) Synthesized
in accordance with general procedure 1. Isolated as a
brown solid (0.129 g, 50%); RF = 0.53 (EtOAc: Et3N 100:1);
M.p.: 68-70 °C; 1H NMR (500.23 MHz, CDCl3): δ 7.91 (d, J =
8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.59-7.53 (m, 1H), 7.35
(ddd, J = 1.0, 7.0, 8.5 Hz, 1H), 6.57 (s, 1H), 4.91 (bs, 1H),
2.87-2.79 (m, 2H), 1.81-1.72 (m, 2H), 1.54 (s, 9H), 1.51-1.40
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The Journal of Organic Chemistry
(m, 2H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR (125.97 MHz,
N-pentyl-2-phenylquinolin-4-amine (9s) Synthesized in
1
2
3
4
5
6
7
8
CDCl3): δ 163.0, 148.4, 147.8, 129.5, 128.7, 123.7, 118.8, 118.1,
100.8, 51.4, 39.6, 32.4, 29.3, 22.7, 14.1; HRMS
accordance with general procedure 2. Isolated as a red-
brown wax (0.131 g, 48 %); RF = 0.35 (cHex:EtOAC:Et3N
4:1:0.01); 1H NMR (500.23 MHz, CDCl3): δ 8.14-8.06 (m,
3H), 7.72 (d, J = 8.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H)m 7.51
(t, J = 7.5 Hz, 2H), 7.47-7.38 (m, 2H), 6.86 (s, 1H), 5.00 (bt,
J = 5.0 Hz, 1H), 3.36 (q, J = 6.5 Hz, 2H), 1.79 (p, J = 7.5 Hz,
2H), 1.53-1.37 (m, 4H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR
(125.97 MHz, CDCl3): δ 158.4, 150.1, 148.6, 141.0, 130.2, 129.1,
128.8, 128.5, 127.5, 124.3, 119.0, 117.8, 96.6, 43.2, 29.3 28.6,
+
(ESI): m/z calcd for C17H25N2 [M+H]+ 257.2007, found:
257.2023.
N-(tert-butyl)-2-decylquinolin-4-amine (9o) Synthesized
in accordance with general procedure 1. Isolated as a red-
brown wax (0.255 g, 75%); RF = 0.62 (EtOAc:Et3N 100:1); 1H
NMR (500.23 MHz, CDCl3): δ 7.92 (d, J = 8.5 Hz, 1H), 7.62
(d, J = 8.5 Hz, 1H), 7.56 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H), 7.34
(t, J = 1.5, 7.5, 7.0 Hz, 1H), 6.57 (s, 1H), 4.91 (bs, 1H), 2.82 (t,
J = 8.0 Hz, 2H), 1.78 (p, J = 8.0 Hz, 2H), 1.53 (s, 9H), 1.46-
1.38 (m, 2H), 1.38-1.32 (m, 2H), 1.31-1.21 (m, 10H), 0.87 (t, J =
9
22.4, 14.0; HRMS (ESI): m/z calcd for C20H23N2 [M+H]+
+
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
58
59
60
291.1851, found: 291.1846.
N-isopropyl-2-(4-(trifluoromethyl)phenyl)quinolin-4-
amine (9t) Synthesized in accordance with general pro-
cedure 2. Isolated as a yellow solid (0.074 g, 24%); RF =
0.39 (cHex:EtOAc:Et3N 4:1:0.01); M.p.: 60-63 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.18 (d, J = 8.0 Hz, 2H), 8.07 (d, J
= 8.5 Hz, 1H), 7.79-7.70 (m, 3H), 7.67 (t, J = 7.5 Hz, 1H),
7.44 (t, J = 7.5 Hz, 1H), 6.86 (s, 1H), 4.93 (bd, J = 7.0 Hz,
1H), 4.05-3.96 (m, 1H), 1.41 (d, J = 6.5 Hz, 6H); 13C NMR
(125.97 MHz, CDCl3): δ 156.8, 149.3, 148.7, 144.4, 130.6 (q, J
= 32.5 Hz), 130.4, 129.4, 127.8, 125.5 (q, J = 4.0 Hz), 124.8,
124.3 (q, J = 271.5 Hz), 119.0, 117.9, 96.8, 40.0, 22.5; HRMS
(ESI): m/z calcd for C19H18N2F3+ [M+H]+ 331.1413, found:
331.1429.
13
7.0 Hz, 3H); C NMR (125.97 MHz, CDCl3): δ 163.0, 148.4,
147.8, 129.5, 128.6, 123.7, 118.8, 118.1, 100.8, 51.3, 39.9, 31.9,
30.2, 29.62, 29.58, 29.56, 29.3, 29.2, 22.6, 14.1; HRMS
+
(ESI): m/z calcd for C23H37N2 [M+H]+ 341.2943, found:
341.2965.
N-isopropyl-2-phenylquinolin-4-amine (9p) Synthesized
in accordance with general procedure 2. Isolated as a red-
brown solid (0.216 g, 81%); RF = 0.16 (cHex:EtOAc:Et3N
4:1:0.05); M.p.: 176 °C; 1H NMR (500.23 MHz, CDCl3): δ
8.12 (m, 3H), 7.72 (d, J = 8.5 Hz, 1H), 7.68-7.61 (m, 1H), 7.51
(t, J = 7.5 Hz, 2H), 7.48-7.38 (m, 2H), 6.89 (s, 1H), 4.87 (bd,
J = 7.0 Hz, 1H), 4.04-3.92 (m, 1H), 1.40 (dd, J = 1.5, 6.5 Hz,
6H); 13C NMR (125.97 MHz, CDCl3): δ 158.4, 149.0, 148.7,
141.1, 130.3, 129.1, 128.7, 128.5, 127.5, 124.2, 119.0, 117.8, 97.0,
Methyl 4-(cyclohexylamino)-2-(3,4,5-trimethoxyphenyl)
quinoline-6-carboxylate (9u) Synthesized in accordance
with general procedure 2. Isolated as a dark yellow solid
(0.167 g, 39%); RF = 0.13 (cHex:EtOAc:Et3N 4:1:0.01); M.p.:
141-143 °C; 1H NMR (500.23 MHz, CDCl3): δ 8.52 (d, J = 2.0
Hz, 1H), 8.20 (dd, J = 2.0, 9.0 Hz, 1H), 8.03 (d, J = 9.0 Hz,
1H), 7.27 (s, 2H), 6.80 (s, 1H), 5.19 (bd, J = 7.0 Hz, 4.11-3.95
(m, 9H), 3.91 (s, 3H), 3.63 (dtt, J = 3.5, 7.0, 10.0 Hz, 1H),
2.24-2.17 (m, 2H), 1.97-1.82 (m, 2H), 1.81-1.68 (m, 2H), 1.52-
1.37 (m, 4H); 13C NMR (125.97 MHz, CDCl3): δ 167.0, 160.3,
153.3, 151.1, 149.9, 139.3, 136.5, 130.2, 128.8, 125.1, 122.7, 117.0,
105.1, 97.1, 60.9, 56.3, 52.3, 51.5, 32.7, 25.6, 24.9; HRMS
(ESI): m/z calcd for C26H31N2O5+ [M+H]+ 451.2220, found:
451.2236.
43.9, 22.5; HRMS (ESI): m/z calcd for C18H19N2 [M+H]+
+
263.1539, found: 263.1556.
N-cyclohexyl-6-fluoro-2-phenylquinolin-4-amine
(9q)
Synthesized in accordance with general procedure 2.
Isolated as a yellow solid (0.229 g, 80%); RF = 0.50
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 146-149 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.09-8.06 (m, 1H), 8.04 (d, J = 8.0
Hz, 2H), 7.51 (d, J = 7.0, 2H), 7.47-7.37 (m, 2H), 7.34 (dd, J
= 2.0, 10.0, 1H), 6.86 (s, 1H), 4.71 (bd, J = 7.5 Hz, 1H), 3.66-
3.56 (m, 1H), 2.20 (dd, J = 4.0, 13.0, 2H), 1.89-1.81 (m, 2H),
1.76-1.70 (m, 1H), 1.53-1.44 (m, 2H), 1.42-1.30 (m, 3H); 13C
NMR (125.97 MHz, CDCl3): δ 159.5 (d, J = 245.0), 157.9 (d, J
= 2.5 Hz), 148.6 (d, J = 5.0 Hz), 145.7, 140.8, 132.5 (d, J = 8.5
Hz), 128.9, 128.6, 127.5, 118.8 (d, J = 25.0 Hz), 118.2 (d, J =
8.0 Hz), 103.4 (d, J = 23.0 Hz), 97.3, 51.3, 32.8, 25.7, 24.8;
HRMS (ESI): m/z calcd for C21H22N2F+ [M+H]+ 321.1757,
found: 321.1776.
N1,N1-diethyl-N4-(2-phenylquinolin-4-yl)pentane-1,4-
diamine (9w) Synthesized in accordance with general
procedure 2. Isolated as a red-brown wax (0.287 g, 79%);
RF = 0.09 (EtOAc:Et3N 100:1); 1H NMR (500.23 MHz,
CDCl3): δ 8.09-8.02 (m, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.67-
7.60 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.47-7.37 (m, 2H),
6.86 (s, 1H), 5.18 (bd, J = 7.5 Hz, 1H), 3.90-3.80 (m, 1H),
2.57 (q, J = 7.0 Hz, 4H), 2.50 (t, J = 7.0 Hz, 2H), 1.85-1.75
(m, 1H), 1.73-1.63 (m, 2H), 1.37 (d, J = 6.5 H, 3H), 1.03 (t, J =
7-chloro-N-isopropyl-2-phenylquinolin-4-amine
(9r)
Synthesized in accordance with general procedure 2.
Isolated as a yellow solid (0.175 g, 60%); RF = 0.47
(cHex:EtOAc:Et3N 4:1:0.01); M.p.: 147-148 °C; 1H NMR
(500.23 MHz, CDCl3): δ 8.11-8.00 (m, 3H), 7.65 (d, J = 9.0
Hz, 1H), 7.53-7.48 (m, 2H), 7.47-7.43 (m, 1H), 7.34(dd, J =
2.0, 9.0 Hz, 1H), 6.85 (s, 1H), 4.88 (bs, 1H), 4.04-3.91 (m,
1H), 1.40 (d, J = 6.5 Hz, 6H); 13C NMR (125.97 MHz, CDCl3):
δ 159.3, 149.4, 149.2, 140.5, 135.0, 129.1, 129.0, 128.6, 127.5,
124.9, 120.6, 116.2, 97.2, 44.1, 22.5; HRMS (ESI): m/z calcd
for C18H18N2Cl+ [M+H]+ 297.1150, found: 297.1163.
13
7.0 Hz, 6H); C NMR (125.97 MHz, CDCl3): δ 158.5, 149.3,
148.8, 141.2, 130.3, 129.1, 128.7, 128.6, 127.5, 124.2, 119.2, 117.9,
96.9, 52.6, 48.2, 46.8, 34.7, 23.8, 20.4, 11.4; HRMS
(ESI): m/z calcd for C24H32N3+ [M+H]+ 362.2584, found:
362.2595.
N4-(3-(benzo[d][1,3]dioxol-5-yl)-6-chloronaphthalen-1-
yl)-N1,N1-diethylpentane-1,4-diamine (9x) Synthesized in
accordance with general procedure 2. Isolated as a yellow-
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brown solid (0.327 g, 78 %); RF = 0.15 (EtOAc:Et3N 99:1);
1.5 Hz, 3H); 13C NMR (125.97 MHz, CDCl3): δ 158.2, 149.4,
M.p.: 48-50 °C; 1H NMR (500.23 MHz, CDCl3): δ 7.98 (d, J
= 2.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 2.0 Hz,
1H), 7.56 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 6.91
(d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 6.01 (s, 2H), 5.25 (bd, J =
7.0 Hz, 1H), 3.79 (hept, J = 6.5 Hz, 1H), 2.53 (q, J = 7.0 Hz,
4H), 2.46 (t, J = 7.0 Hz, 2H), 1.81-1.65 (m, 2H), 1.65-1.59 (m,
2H), 1.34 (d, J = 6.5 Hz, 3H), 1.00 (t, J = 7.0 Hz, 6H); 13C
NMR (125.97 MHz, CDCl3): δ 158.6, 149.5, 149.3, 148.5,
148.0, 135.1, 134.8, 128.9, 124.4, 121.5, 120.9, 116.3, 108.2,
107.9, 101.2, 96.5, 52.4, 48.2, 46.7, 34.5, 23.8, 20.2, 11.3;
HRMS (ESI): m/z calcd for C25H31N3O2Cl+ [M+H]+
440.2093, found: 440.2092.
148.8, 138.3, 133.7, 133.4, 130.3, 129.3, 128.7, 128.2, 127.7,
126.9, 126.4, 126.1, 125.4, 124.4, 119.0, 117.9, 97.0, 48.3, 38.9,
37.1, 27.9, 24.0, 22.60, 22.58, 20.4; HRMS (ESI): m/z calcd
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2
3
4
5
6
7
8
+
for C27H31N2 [M+H]+ 383.2475, found: 383.2490.
Ethyl 4-((7-chloro-2-phenylquinolin-4-yl)amino)piperi-
dine-1-carboxylate (9ab) Synthesized in accordance with
general procedure 2. Isolated as a yellow-orange solid
(0.277 g, 68%); RF = 0.11 (cHex:EtOAc: Et3N 4:1:0.01); M.p.:
186-187 °C; 1H NMR (500.23 MHz, CDCl3): δ 8.07 (d, J =
2.0 Hz, 1H), 8.05-8.03 (m, 1H), 8.03-8.01 (m, 1H), 7.65 d, J =
9.0 Hz, 1H), 7.68-7.62 (m, 2H), 7.50-7.42 (m, 1H), 7.35 (dd,
J = 2.0, 9.0 Hz, 1H), 6.85 (s, 1H), 4.95 (bs, 1H), 4.32-4.25 m,
2H), 4.17 (q, J = 7.0 Hz, 2H), 3.80 (tdt, J = 4.0, 7.5, 10.5 Hz,
1H), 3.08 (t, J = 12.5 Hz, 2H), 2.28-2.14 (m, 2H), 1.64-1.48
(m, 2H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR (125.97 MHz,
CDCl3): 159.3, 155.4, 148.7, 140.3, 135.3, 129.3, 129.1,128.7,
127.6, 125.2, 120.6, 116.2, 97.2, 61.6, 49.7, 42.6, 31.7, 14.7;
HRMS (ESI): m/z calcd for C23H25N3O2Cl+ [M+H]+
410.1625, found: 410.1630.
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N4-(7-chloro-2-phenylquinolin-4-yl)-N1,N1-
diethylpentane-1,4-diamine (9y) Synthesized in accord-
ance with general procedure 2. Isolated as a red-brown
wax (0.326 g, 82%); RF = 0.14 (EtOAc: Et3N 99:1); 1H NMR
(500.23 MHz, CDCl3): δ 8.08-8.02 (m, 3H), 7.67 (d, J = 9.0
Hz, 1H), 7.50 (t, J = 7.0 Hz, 2H), 7.48-7.40 (m, 1H), 7.33
(dd, J = 2.0, 9.0 Hz, 1H), 6.85 (s, 1H), 5.29 (bd, J = 7.0 Hz,
1H), 3.82 (hept, J = 6.5, 1H), 2.54 (q, J = 7.0 Hz, 4H), 2.47 (t,
J = 7.0 Hz, 2H), 1.83-1.74 (m, 1H), 1.74-1.60 (m, 3H), 1.36 (d,
J = 6.5 Hz, 3H), 1.01 (t, J = 7.0 Hz, 6H); 13C NMR (125.97
MHz, CDCl3): δ 159.4, 149.6, 149.5, 140.7, 134.9, 129.1, 129.0,
128.6, 127.5, 124.7, 120.9, 116.4, 97.1, 52.5, 48.3, 46.8, 34.6,
23.8, 20.3, 11.3; HRMS (ESI): m/z calcd for C24H31N3Cl+
[M+H]+ 396.2195, found: 396.2213.
N,N-diethyl-4-isocyanopentan-1-amine (7w) A solution
of N1,N1-diethylpentane-1,4-diamine (3.87 mL, 20 mmol)
in ethyl formate (4.82 mL, 60 mmol) was refluxed for 16
h., after which the solvent was removed in vacuo. To a
solution of the crude product (3.00 g, 16.1 mmol) in dry
CH2Cl2 (80 mL) was added DIPEA (7.01 mL, 40.25 mmol)
and cooled to -40°C. Triphosgene (1.67 g, 5.64 mmol) was
added portionwise, after which the mixture was allowed
to warm to 0°C, and stirred for 2h. The crude product was
poured in water (80 mL), and the organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo to afford
the title compound as a pale yellow liquid (2.370 g, 88%);
RF = 0.11 (EtOAc:MeOH:Et3N 9:1:0.09); 1H NMR (500.23
MHz, CDCl3): δ 3.71-3.59 (m, 1H), 2.52 (q, J = 7.0 Hz, 4H),
2.44 (t, J = 7.0 Hz, 2H), 1.70-1.52 (m, 4H), 1.37 (dt, JHN = 2.0
Hz, JHH = 7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H); 13C (125.97
MHz, CDCl3): δ 154.2 (t, JC(sp)N = 5.0 Hz), 52.0, 50.3 (t,
JC(sp3)N = 5.5 Hz), 46.8, 34.8, 23.3, 21.8, 11.6; HRMS
(ESI): m/z calcd for C10H21N2+ [M+H]+ 169.1695, found:
169.1705.
N4-(2-cyclohexyl-7-fluoroquinolin-4-yl)-N1,N1-
diethylpentane-1,4-diamine (9z) Synthesized in accord-
ance with general procedure 2. Isolated as a red-brown
wax (0.268 g, 70 %); RF = 0.14 (EtOAc: Et3N 99:1); 1H NMR
(500.23 MHz, CDCl3): δ 7.71-7.64 (m, 1H), 7.53 (dt, J = 2.0,
10.5 Hz, 1H), 7.06 (t, J = 8.5 Hz, 1H), 6.28 (d, J = 2.0 Hz,
1H), 5.16 (bd, J = 7.0 Hz, 1H), 3.72 (p, J = 6.5 Hz, 1H), 2.72
(td, J = 3.0, 12.0 Hz, 1H), 2.52 (q, J = 7.0 Hz, 4H), 2.45 (t, J =
7.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.87-1.81 (m, 2H), 1.77-1.69
(m, 2H), 1.65-1.50 (m, 5H), 1.42 (q, J = 11.5 Hz, 2H), 1.34-1.24
(m, 1H), 1.30 (d, J = 6.5 Hz, 3H), 1.00 (td, J = 2.0, 7.0, 6H);
13C NMR (125.97 MHz, CDCl3): δ 168.7, 162.9 (d, J = 247.5
Hz), 149.6 (d, J = 12.5 Hz), 149.3, 121.5 (d, J = 10.5 Hz), 114.8,
113.1 (d, J = 25.0 Hz), 112.8 (d, J = 20.0 Hz), 96.3, 52.5, 48.0,
47.9, 46.7, 34.5, 32.89, 32.86, 26.5, 26.0, 23.7, 20.2, 11.2;
HRMS (ESI): m/z calcd for C24H37N3F+ [M+H]+ 386.2958,
found: 386.2970.
ethyl 4-isocyanopiperidine-1-carboxylate (7ab) Ethyl 4-
aminopiperidine-1-carboxylate (4.03 mL, 29.0 mmol) was
refluxed in ethyl formate (7.01 mL, 87.1 mmol) for 16 h.,
after which the solvent was removed in vacuo. To a solu-
tion of the crude formamide (3.10 g, 15.5 mmol) in dry
CH2Cl2 (45 mL) was added Et3N (4.32 mL, 31 mmol). The
solution was cooled to -40 °C, after which triphosgene
(1.61 g, 5.52 mmol) was added portionwise. The resulting
mixture was slowly warmed to room temperature, and
stirred for 3 h. Hereafter, the reaction was quenched with
ice-water (50 mL), and the resulting biphasic system was
separated. The organic layer was washed with 1 M HCl,
saturated NaHCO3, and water, dried over Na2SO4, filtered,
and concentrated in vacuo, affording the target isocyanide
as a pale yellow oil. (2.471 g, 88 %); RF = 0.16 (cHex:EtOAc:
Et3N 4:1:0.01); 1H NMR (500.23 MHz, CDCl3): δ 4.12 (q, J =
N-(6-methylheptan-2-yl)-2-(naphthalen-2-yl)quinolin-4-
amine (9aa) Synthesized in accordance with general
procedure 2. Isolated as a red-brown solid (0.294 g, 77 %);
RF = 0.26 (cHex:EtOAc: Et3N 4:1:0.01); M.p.: 128-129 °C; 1H
NMR (500.23 MHz, CDCl3): δ 8.57-8.53 (m, 1H), 8.26 (dd,
J = 2.8, 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.01-7.98 m,
1H), 7.98 (d, J = 9.0 Hz, 1H), 7.92-7.87 (m, 1H), 7.76-7.72
(m, 1H), 7.67 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H), 7.54-7.49 (m,
2H), 7.44 (ddd, J = 1.5, 7.0, 8.5 Hz, 1M), 7.01 (s, 1H), 4.90
(bd, J = 7.5 Hz, 1H), 3.89 (hept, J = 6.5 Hz, 1H), 1.81-1.73 (m,
1H), 1.70-1.53 (m, 3H), 1.53-1.44 (m, 2H), 1.39 (d, J = 6.5 Hz,
3H), 1.30-1.24 (m, 2H), 0.90 (d, J = 1.5 Hz, 3H), 0.89 (d, J =
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(12) Brouwer, C.; Jenko, K.; Zoghbi, S. S.; Innis, R. B.; Pike, V.
7.0 Hz, 2H), 3.89-3.81 (m, 1H), 3.60 (ddd, J = 3.5, 8.0, 14.0
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W. J. Med. Chem. 2014, 57, 6240.
Hz, 2H), 3.54-3.44 (m, 1H), 1.93-1.83 M, 2H), 1.83-1.75 (m,
2H), 1.25 (t, J = 7.0 Hz, 3H); 13C (125.97 MHz, CDCl3): 156.2
(t, J = 5.0 Hz), 155.2, 61.6, 49.3 (t, J = 6.0 Hz), 40.0, 31.2,
(13) Singh, S.; Roy, K. K.; Khan, S. R.; Kashyap, V. K.; Sharma,
A.; Jaiswal, S.; Sharma, S. K.; Krishnan, M. Y.; Chaturvedi, V.;
Lal, J.; Sinha, S.; Dasgupta, A.; Srivastava, R.; Saxena, A. K.
Bioorg. Med. Chem. 2015, 23, 742.
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14.6;
HRMS
(ESI): m/z
calcd
for
C9H14N2O2Na+ [M+Na]+ 205.0944, found: 205.0955.
Supporting Information
The Supporting Information is available free of charge on the
9
ACS Publications website.
1H and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
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Corresponding Author
* E. Ruijter: e.ruijter@vu.nl *R.V.A. Orru: r.v.a.orru@vu.nl
Author Contributions
The manuscript was written through contributions of all
authors.
ORCID
Bert U. W. Maes: 0000-0003-0431-7606
Eelco Ruijter:
0000-0002-1105-3947
Notes
The authors declare no competing financial interest.
Acknowledgements
We thank Elwin Janssen for NMR support and mainte-
nance. The research leading to these findings has received
financial support from the Netherlands Organization for
Scientific Research (NWO).
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