Efficient [5+1] synthesis of 4-quinolones by domino amination and conjugate addition reactions of 1-(2-fluorophenyl)prop-2-yn-1-ones with amines

Article abstract of DOI:10.1055/s-0032-1316826

A catalyst-free synthetic approach is described for the synthesis of 4-quinolone derivatives through a tandem amination/conjugated Michael addition sequence of 1-(2-fluorophenyl)prop-2-yn-1-one derivatives. The [5+1]-cyclization proceeds efficiently at a high temperature under an inert atmosphere with lithium carbonate as a base, and it provides a practical route to a diverse range of 4-quinolones. The mechanism was studied in details and several of the intermediates were isolated. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316826

PAPER
▌205
paper
Efficient [5+1] Synthesis of 4-Quinolones by Domino Amination and Conjugate
Addition Reactions of 1-(2-Fluorophenyl)prop-2-yn-1-ones with Amines
4-Quinolones by Domino Amination and Conjugate Addition Reactions
Viktor O. Iaroshenko,*a,b Satenik Mkrtchyan,a Alexander Villingera
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)49864112; E-mail: viktor.iaroshenko@uni-rostock.de
b
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
E-mail: iva108@googlemail.com
Received: 14.09.2012; Accepted after revision: 19.11.2012
O
N
O
O
N
O
Abstract: A catalyst-free synthetic approach is described for the
synthesis of 4-quinolone derivatives through a tandem amina-
tion/conjugated Michael addition sequence of 1-(2-fluorophe-
nyl)prop-2-yn-1-one derivatives. The [5+1]-cyclization proceeds
efficiently at a high temperature under an inert atmosphere with
lithium carbonate as a base, and it provides a practical route to a di-
verse range of 4-quinolones. The mechanism was studied in details
and several of the intermediates were isolated.
F
F
OH
OH
N
N
HN
OMe
N
O
Me
ciprofloxacin
(antibiotic)
II
levofloxacin
(antibiotic)
I
O
N
O
O
N
O
F
Key words: quinones, ketones, domino reactions, aminations,
Michael additions, heterocycles
F
F
OH
OH
H
H
N
N
H
N
OMe
Functionalized quinolines are attractive compounds for
use in drug discovery because many of them exhibit ex-
cellent biological activities.1 It is well known that the
quinoline core exists in many natural products.2,3 Seven of
the 200 best-selling drugs in the world contain a quinoline
or quinolone framework in the form of the parent hetero-
cycle or a reduced derivative thereof. For example, oxoin-
deno[1,2-b]quinoline derivatives show strong binding to
DNA and efficient inhibition of DNA topoisomerase I.
These properties are associated with their pronounced an-
ticancer activities.4 The drug irinotecan is a well-known
representative of this family of compounds that prevents
DNA from unwinding. In chemical terms, it is a semisyn-
thetic analogue of the natural alkaloid camptothecin.3
H
H2N
IV
NH
moxifloxacin
(antibacterial agent)
trovafloxacin
(antibiotic)
III
F
Figure 1 Marketed drugs containing a quinolone framework
As a continuation of our ongoing research program on the
design and synthesis of drug-like scaffolds containing a
pyridine core,9 we have attempted to develop a new and
efficient strategy for the assembly of functionalized
quinolin-4-ones. Recent advances in the synthesis of pyr-
idines, quinolines, and fused pyridines by [5 + 1]-cycliza-
tion strategies include several efficient methods for the
construction of such heterocyclic scaffolds.10
Other quinoline-containing drugs5 include mefloquine,5a–c
montelukast,5d,e and aripiprazole.5f–j Mefloquine is a leu-
kotriene receptor antagonist that is used for maintenance
treatment of asthma and to relieve symptoms of seasonal
allergies. Aripiprazole represents a class of antidepressant
agents used in the treatment of schizophrenia, bipolar dis-
order, and clinical depression. Additionally, it shows anti-
psychotic action. Fluoroquinolones occupy a special
position among drugs containing a quinoline core. The
four representatives shown in Figure 1 are among the 200
best-selling drugs in the world. Quinoline derivatives
have also found applications as chiral ligands for organo-
catalysis.6 In view of the importance of quinolines, contin-
ual efforts have been made to develop new methods for
the synthesis of these heterocyclic scaffolds.7,8
On the basis of our previous experience,10m we hypothe-
sized that the quinolin-4-one framework might be assem-
bled in a catalyst-free manner from phenylpropyn-1-ones
containing a good leaving group in the ortho-position of
the aryl part of the molecule. It is known9c,11 that fluoro or
nitro groups12 located in the position ortho or para to an
electron-withdrawing substituent can be easily substituted
by a range of soft or strong nucleophiles. Many nucleo-
philic substitution reactions of aromatic and heteroaro-
matic cores in which fluorine serves as the leaving group
are known.
Here, we describe the development of a strategy for the
synthesis of functionalized quinolin-4-ones by a two-
component reaction of 1-(2-fluorophenyl)prop-2-yn-1-
ones with amines. We examined this reaction for a series
of 1-(2-fluorophenyl)prop-2-yn-1-one derivatives 3, ob-
tained in good to excellent yields from commercially
available alkynes and fluorinated benzoyl chlorides 1 by a
Sonogashira reaction (Scheme 1).
SYNTHESIS 2013, 45, 0205–0218
Advanced online publication: 07.12.2012
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DOI: 10.1055/s-0032-1316826; Art ID: SS-2012-Z0720-OP
© Georg Thieme Verlag Stuttgart · New York

206
V. O. Iaroshenko et al.
PAPER
O
F
O
O
F
O
R3 NH2
4
R1
R1
Cl
R1
R1
R2
i
R2
R2
2
i
R2
3
N
R3
F
5
1
3
R3 NH2
ii
3a R1 = H, R2 = Ph (88%)
4
3b R1 = H, R2 = 4-t-BuC6H4 (78%)
3c R1 = 5-F, R2 = 4-t-BuC6H4 (84%)
3d R1 = 5-F, R2 = 4-MeC6H4 (91%)
3e R1 = 4-F, R2 = 4-MeC6H4 (97%)
3f R1 = 6-F, R2 = Ph (70%)
H
R3
R2
O
N
O
F
HN
R1
R1
NH
R3
3g R1 = 6-F, R2 = 4-MeC6H4 (73%)
3h R1 = 6-F, R2 = 4-t-BuC6H4 (80%)
3i R1 = 6-F, R2 = (CH2)4Me (70%)
3j R1 = 3,4,5,6-F, R2 = 4-t-BuC6H4 (75%)
6
R2
D
R3
i
Scheme 1 Reagents and conditions: (i): PdCl2(PPh3)2 (2 mol%), CuI
(4 mol%), THF, dry argon.
R3
R2
R3
R2
O
HN
O
HN
R1
R1
As a first step, we treated the model compound 3a with
two equivalents of (2-phenylethyl)amine in N, N-dimeth-
ylformamide at 140 °C in the presence of potassium car-
bonate as a base. The first trial gave an 18% yield of the
desired 1-substituted quinolin-4-one 5a after 10 hours of
heating (Table 1, entry 1). The crucial conditions for this
cyclization appeared to be the temperature, the solvent,
and the base–reaction time combination. The best yields
were obtained by conducting the reaction for 24 hours in
N,N-dimethylacetamide at 160 °C with lithium carbonate
as the base. When the lithium salt was used, the yield of
5a increased from 51% to 89% (entries 6 and 7). We be-
lieve that the lithium(1+) ion coordinates with the fluorine
atom, facilitating the nucleophilic substitution (Scheme
2). Furthermore, when we used 1.2 equivalents of the
amine, the yield of 5a decreased to 71%.
H2N R3
F
NH
R3
Li
A
C
R3
O
HN
R2
R1
NH2 R3
F
Li
B
Scheme 2 Reagents and conditions: (i) Li2CO3, DMA, 160 °C, 24–
30 h; (ii) DMF, 100 °C, 10 h.
lent yields of the corresponding products, whereas ani-
lines gave good yields. However, the reaction failed in the
case of electron-deficient heteroaromatic amines such as
benzo[d]thiazol-2-amine, pyrimidin-2-amine, or pyridin-
2-amine. In general, we observed a slight deviation from
the optimal reaction time of 24 hours for some amines.
The reaction was therefore conducted for 30 hours and
monitored by thin-layer chromatography. This allowed us
to achieve complete conversion of the starting 1-(2-fluo-
rophenyl)prop-2-yn-1-ones 3a and 3b.
Table 1 Optimization of the Synthesis of 5a
Conditions
Temp
(°C)
Time
(h)
Yield (%)
of 5aa
1
2
3
4
5
6
7
8
4 (2 equiv), DMF, K2CO3
4 (2 equiv), DMF, Li2CO3
4 (2 equiv), DMA, K2CO3
4 (2 equiv), DMA, Li2CO3
4 (2 equiv), DMA, Li2CO3
4 (2 equiv), DMA, K2CO3
4 (2 equiv), DMA, Li2CO3
140
140
160
160
160
160
160
10 h
10 h
12 h
12 h
18 h
24 h
24 h
24 h
18
25
35
58
73
51
89
75
These results gave us an incentive to test another good
leaving group that is often used in aromatic nucleophilic
substitution reactions, namely the nitro group. Bearing in
mind that the nitro group is often considered to be a better
leaving group than the fluoro group, we studied the reac-
tion of the nitro ynone 7 with aliphatic and aromatic
amines 4 (Scheme 3). Nitro compound 7 was synthesized
by same protocol as that which we developed for the syn-
thesis of compounds 3 through a Sonogashira coupling re-
action of commercially available 2-nitrobenzoyl chloride.
The cyclization reactions could be performed under mild-
er conditions (N,N-dimethylformamide, potassium car-
bonate, 130 °C). The presence of the nitro group did not
increase the yields in comparison with those of 5a–f, but
nevertheless the 4-quinolones were obtained in good
yields (Table 3). However, this variant lacks diversity
with regard to the availability of substrates bearing a nitro
group at the 2-position of the aryl moiety.
4 (1.2 equiv), DMA, Li2CO3 160
a Yield of pure compound.
Having identified the optimal conditions, we investigated
the scope of the reaction with respect to the amine 4 and
the fluorine-containing substrate 3. By using the opti-
mized conditions, we conducted a series of tandem [5+1]-
cyclizations of various amines 4 with fluoro ynones 3a
and 3b to give the corresponding quinolin-4-ones 5a–h
(Table 2). Generally, aliphatic amines gave good to excel-
Synthesis 2013, 45, 205–218
© Georg Thieme Verlag Stuttgart · New York

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4-Quinolones by Domino Amination and Conjugate Addition Reactions
207
with the second fluorine in a meta-position did not react
with amines and, in this case, the reaction gave the corre-
sponding quinolin-4-ones 5i–m which contain a fluorine
group in the 6-position.
Table 2 Synthesis of Quinolones 5
Product Fluoro
compound
R1 R2
R3
Yield
(%)a
5a
5b
5c
5d
5e
5f
3a
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
(CH2)2Ph
(CH2)3Ph
89 (79)b
86 (80)b
Nevertheless, double substitution occurred only with ali-
phatic amines. The use of anilines under our standard re-
action conditions did not result in substitution of the
second fluoro group, and products 5n–t were obtained.
However, this result gave us the opportunity of substitut-
ing the second activated fluorine in compounds 5o, 5r,
and 5s with aliphatic amines to give the quinolones 8j, 8k,
and 9b, respectively.
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
3e
3e
3f
CH2-4-MeOC6H4 87 (77)b
(CH2)4Me
(CH2)5Me
84 (79)b
89 (78)b
3,5-(MeO)2C6H3 74 (70)b
On analyzing the reaction mixtures from 5s and 5t, we de-
tected the disubstituted products 8f and 8i, respectively,
but their yields never exceeded 3–5%. Next, we were in-
terested in developing the procedure to introduce a second
molecule of the aniline. We therefore treated 3g, 3i, 5s,
and 5t, with 4-ethylaniline or 4-methoxyaniline under
harsher reaction conditions by using N-methyl-2-pyrrol-
idone as the solvent and conducting the reactions at
185 °C for at least 30 h. This resulted in the synthesis of
4-quinolones 8f (entry 6) and 8i (entry 9).
5g
5h
5i
4-t-BuC6H4 4-ClC6H4
4-t-BuC6H4 4-BrC6H4
75 (70)c
73 (64)c
6-F 4-t-BuC6H4 3,5-(MeO)2C6H3 77 (60)d
5j
6-F 4-t-BuC6H4 4-MeOC6H4
78 (64)d
85
5k
5l
6-F 4-Tol
6-F 4-Tol
6-F 4-Tol
7-F 4-Tol
7-F 4-Tol
5-F Ph
(CH2)5Me
(CH2)2Ph
88
5m
5n
5o
5p
5q
5r
5s
5t
(CH2)3Ph
83
Alkyne derivative 3j containing a pentafluorophenyl
group failed to react under any of the previously men-
tioned reaction conditions, while its reaction with amines
gave complex inseparable mixtures. We failed in our at-
tempts to isolate at least one component in a pure form.
4-t-BuC6H4
3,5-Me2C6H3
3,5-Me2C6H3
75
79
77
3h
3g
3g
3i
5-F 4-t-BuC6H4 3,5-(MeO)2C6H3 73
To demonstrate the scope of the reaction we also investi-
gated the reactions of diamines, which gave the corre-
sponding N,N′-linked 4-quinolones 10 (Figure 2). This
result shows that our method might be useful, for instance,
in the construction of quinolin-4-one-group-containing
dendrimers.
5-F 4-Tol
3,5-Me2C6H3
4-EtC6H4
71
70
72
5-F 4-Tol
5-F (CH2)4Me
4-MeOC6H4
a Yield of pure compound is shown in parentheses.
b This compound was obtained starting from 7.
c This compound was obtained starting from 6b.
d This compound was obtained starting from 6a.
The structures of the quinolin-4-ones 5, 8, and 9 was es-
tablished unambiguously by one- and two-dimensional
NMR spectrometric methods and the structures of scaf-
folds 5 and 8 were corroborated by X-ray diffraction anal-
ysis (Figures 1–3 in the Supporting Information).13 On the
basis of the examples of the molecular structures of com-
pounds 5g, 5q, and 8b, the structure of the quinolin-4-one
scaffold was established unambiguously.
To obtain an insight into the reaction mechanism, we at-
tempted to detect possible intermediates of the cyclization
reaction. When we performed the reaction in N,N-dimeth-
ylformamide at 100 °C for ten hours, a single spot that
was different from the product or the starting materials
was identified by thin-layer chromatographic analysis.
We also observed similar spots after the addition of two
equivalents of lithium carbonate. These intermediates
were isolated and their structures were examined by one-
and two-dimensional NMR methods and shown to be
those of compounds 6a and 6b (Figure 3). Under the stan-
dard reaction conditions with one equivalent of the appro-
priate amine, the formation of the corresponding
quinolone was observed after 24 hours. It is also worth-
while mentioning that, in the case of bulky amines such as
1-adamantylamine, the reaction under standard conditions
O
O
R3 NH2
i
4
Ph
NO2
N
R3
Ph
7
5a–f
Scheme 3 Reagents and conditions: (i) K2CO3, DMF, 130 °C, 6 h.
When alkynes 3g–i, which contain a second fluorine
atom, were investigated, we observed an interesting phe-
nomenon. When the second fluorine was located in a
position ortho or para to the carbonyl group, it was sub-
stituted by an amine to give the amino-substituted quino-
lones 8a–i and 9a (Table 3, entries 1–9 and 12). Substrates
© Georg Thieme Verlag Stuttgart · New York
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208
V. O. Iaroshenko et al.
PAPER
Table 3 Synthesis of Quinolones 8 and 9
Entry
Product
Fluoro compound R2
R3
R4
Yield (%)a
1
8a
8b
8c
8d
8e
8f
3h
3h
3h
3g
3g
3g
3i
4-t-BuC6H4
(CH2)3Ph
(CH2)3Ph
82
85
93
2
4-t-BuC6H4
4-t-BuC6H4
4-Tol
CH2-4-MeOC6H4
(CH2)2Ph
CH2-4-MeOC6H4
(CH2)2Ph
3
4
(CH2)2-3,4-(MeO)2C6H3
(R)-CH(Ph)Me
4-EtC6H4
(CH2)2-3,4-(MeO)2C6H3 85
5
4-Tol
(R)-CH(Ph)Me
4-EtC6H4
40b
6
4-Tol
72c (79)c,d
7
8g
8h
8i
(CH2)4Me
(CH2)4Me
(CH2)4Me
4-Tol
(CH2)2Ph
(CH2)2Ph
82
8
3i
(CH2)3Ph
(CH2)3Ph
75
9
3i
4-MeOC6H4
3,5-(Me)2C6H3
4-EtC6H4
4-MeOC6H4
(CH2)2Ph
74c (80)c,d
10
11
12
13
8j
3g
3g
3g
3g
97
84
33b
79
8k
9a
9b
4-Tol
(CH2)2Ph
4-Tol
(R)-CH(Ph)Me
3,5-(Me)2C6H3
(R)-CH(Ph)Me
(CH2)5Me
4-Tol
a Yield of pure compound.
b In this case reaction took 60 h.
c In NMP at 185 °C for 30 h under argon.
d This compound was obtained starting from 5s or 5t.
R4
Ph
O
O
F
HN
NH
O
F
HN
R4
N
R3
R2
O
F
HN
N
R3
R2
9
6a (74%)
8
6b (81%)
Ph
NH
O
HN
Ph
O
F
O
HN
Ph
N
N
O
11a (69%)
10a (49%)
Ph
N
F
F
H
F
11b (64%)
F
Figure 3 Reagents and conditions: (6): Li2CO3, DMF, 100 °C, 10 h;
(11): Li2CO3, DMF, 130 °C, 15 h.
F
O
N
N
gave compound 6b as the single product. The reaction
failed when the open-chain product 6b was subjected to
harsh conditions such as treatment with potassium car-
bonate in N-methyl-2-pyrrolidone at 190 °C or in diphe-
nyl ether at 220 °C. In contrast, the reaction of 6b with
two equivalents of 4-chloroaniline or 4-bromoaniline
gave compounds 5g and 5h in 70% and 64% yield, respec-
tively. The same reactivity was observed for 6a with 3,5-
dimethoxyaniline or 4-methoxyaniline, which gave com-
pounds 5i and 5j, respectively. Finally, the structure of
compound 6b was established by X-ray crystal structure
analysis (Figure 4 in the Supporting Information).13
O
10b (71%)
Figure 2 Reagents and conditions: For 8 and 9: Li2CO3, DMA,
160 °C, 24–30 h; for 10: Li2CO3, DMA, 160 °C, 60 h.
Synthesis 2013, 45, 205–218
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4-Quinolones by Domino Amination and Conjugate Addition Reactions
209
trometry (MS): Finnigan MAT 95 XP (electron ionisation EI, 70
eV). High-resolution MS (HRMS): Finnigan MAT 95 XP. Only the
measurements with an average deviation from the theoretical mass
of ± 2 mDa were accounted as correct. Infrared spectroscopy (IR):
Nicolet 550 FT-IR spectrometer with ATR sampling technique for
solids as well as liquids. Signal characterization: w = weak,
m = medium, s = strong. X-ray crystallography: STOE imaging
plate diffraction systems with monochromatic Mo-K radiation. El-
emental analysis (EA): Leco 932 C, H, N, S. UV/Vis spectroscopy:
Lambda 2 (Perkin-Elmer). Melting point determination (mp):
Micro-Hot-Stage GalenTM III Cambridge Instruments. The melting
points are not corrected. Thin layer chromatography (TLC): Merck
Silica 60 F254 aluminum-backed plates from Macherey-Nagel. De-
tection with UV light at 254 nm and afterwards development with
vanillin–sulfuric acid solution (6 g vanillin, 2.5 mL concd H2SO4,
250 mL EtOH).33 Column chromatography: Separation on Fluka
silica gel 60 (0.063–0.200 mm, 70–320 mesh). Eluents were dis-
tilled before use. Alkynes 2 and amines 4 are commercially avail-
able compounds.
On the basis of these results, we believe that the one-pot
synthesis of 4-quinolones 5 proceeds by reaction of al-
kynes 3 with amines 4 to give intermediates 6, which can
be isolated and identified (Scheme 2). Subsequent coordi-
nation of the lithium cation onto a fluorine atom gives in-
termediate A, which undergoes an aromatic nucleophilic
substitution involving Meisenheimer complex B. Subse-
quent elimination of the fluorine anion in the form of lith-
ium fluoride gives intermediate C. This undergoes an
intermolecular Michael addition via intermediate D to
give the quinolin-4-one 5.
To obtain additional support for this mechanism, we treat-
ed bulky (R)-(+)-(1-phenylethyl)amine with alkyne 3e.
We chose the enantiomerically pure R-enantiomer to
avoid formation of any diastereomeric pairs when two
molecules of amine added to the alkyne moiety. Com-
pound 11a was obtained as a single product. It is neces-
sary to admit that sterically less-hindered amines reacted
with 3 to give 5 directly, and the isolation of intermediates
C was not possible, even when the reaction was conducted
under milder conditions.
The quinolin-4-one formation reaction is extremely sensitive to the
quality of the reagents and to the presence of moisture in solvents,
on glassware, and in the Li2CO3. The amines should also be dry.
Dried solvents and anhyd Li2CO3 should be used because the pres-
ence of H2O markedly decreases the overall yields.
1-(2-Fluorophenyl)prop-2-yn-1-ones 3 and 1-(2-Nitrophenyl)-3-
phenylprop-2-yn-1-ones 7: General Procedure
In contrast, when 1-(2,6-difluorophenyl)-3-(4-tolyl)prop-
2-yn-1-one (3g), which contains a second activated fluo-
rine atom in the para-position, was treated with (R)-(+)-
(1-phenylethyl)amine, formation of the intermediate 11b
(Figure 3) was observed. Furthermore, by using our stan-
dard reaction conditions and two equivalents of the corre-
sponding amine, intermediates 11 reacted to form the
quinolin-4-ones 8e and 9a. As mentioned above, in the
case of alkyne 3j, which contains five fluorine atoms, re-
action with any type of amine always resulted in the for-
mation of a complex mixture of inseparable products. The
structure of the important intermediate 11a was estab-
lished by X-ray crystal structure analysis (Figure 5 in the
Supporting Information).13
A Schlenk flask was charged with PdCl2(PPh3)2 (0.02 equiv) and
CuI (0.04 equiv) then degassed and backfilled with argon. THF (20
mL/g) and the appropriate 2-fluorobenzoyl chloride derivative 1 (1
equiv) or 2-nitrobenzoyl chloride derivative were added. When this
had dissolved, Et3N (1.5 equiv, previously purged with argon) was
added, and the flask was degassed and refilled with argon. The de-
gassing/refilling procedure was repeated three times to ensure that
the reaction was not affected by O2 from the air. The appropriate al-
kyne 2 was then added (1.3 equiv) and the mixture was stirred for
15 h at r.t. When the reaction was complete (TLC), distilled H2O
was added and the mixture was extracted with CH2Cl2. The organic
layers were collected, dried (Na2SO4), and concentrated to give a
residue that was purified by column chromatography [silica gel,
heptane–EtOAc (30:1)].
1-(2-Fluorophenyl)-3-phenylprop-2-yn-1-one (3a)
Yellow oil; yield: 3.94 g (88%).
In conclusion, we examined the domino reaction of 1-(2-
fluorophenyl)prop-2-yn-1-ones 3 with aliphatic and aro-
matic amines 4 in detail. The reaction provides a practical
synthetic route to a set of functionalized 1-substituted
quinolin-4-ones. The mechanism of this transformation
was investigated and a number of intermediates were iso-
lated and identified. The scope and limitations of the reac-
tion have been studied.
IR (ATR): 3063 (w), 2195 (s), 1627 (s), 1606 (s), 1482 (s), 1453 (s),
1306 (s), 1228 (m), 1203 (s), 1154 (m), 1101 (m), 1026 (m), 1010
(s), 994 (s), 839 (m), 778 (m), 747 (s), 686 (s), 617 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.97–7.03 (m, 1 H, CHAr), 7.08–
7.14 (m, 1 H, CHAr), 7.20–7.32 (m, 3 H, CHAr), 7.37–7.50 (m, 3 H,
CHAr), 7.95 (dt, 3J = 7.6 Hz, 4J = 1.7 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 88.1 (C), 92.5 (t, 4J = 3.1 Hz, C),
3
4
116.7 (d, J = 22.2 Hz, CHAr), 119.5 (C), 123.8 (d, J = 4.0 Hz,
4
CH), 125.1 (d, J = 7.5 Hz, C), 128.3, 130.6, 131.4, 132.7 (CH),
The dry solvents DMF, DMA, NMP, and THF were purchased di-
rectly from Acros Organics as AcroSeal bottles. Other solvents
were purified by distillation. All reactions were carried out under an
inert atmosphere.
135.3 (d, 3J = 8.8 Hz, CH), 159.9, 163.3, 173.5 (C).
19F NMR (282 MHz, CDCl3): δ = –111.3.
MS (GC, 70 eV): m/z (%) = 224 (58) [M+], 196 (100), 129 (72).
1H and 13C NMR spectroscopy: Bruker AV 300 and Bruker AV 400
spectrometers. References: 0.00 ppm for TMS, 7.26 ppm for CDCl3
(1H NMR) and 0.00 ppm for TMS, 77.00 ppm for CDCl3 (13C
NMR). The DEPT method was used for determining the presence
of primary, secondary, tertiary and quaternary carbon atoms. The
HRMS (EI): m/z [M+] calcd for C15H9FO: 224.06319; found:
224.063269.
3-(4-tert-Butylphenyl)-1-(2-fluorophenyl)prop-2-yn-1-one (3b)
Yellow oil; yield: 4.37 g (78%).
1H NMR spectra were measured with standard number of scans; 13
C
IR (ATR): 2162 (w), 2193 (s), 1629 (s), 1606 (s), 1504 (w), 1481
(m), 1453 (s), 1364 (w), 1305 (s), 1267 (m), 1207 (s), 1187 (m),
1154 (m), 1100 (m), 1006 (s), 834 (s), 776 (m), 749 (s), 679 (m),
637 (s), 564 (s) cm–1.
NMR spectra were measured with standard number of scans or
when necessary, with 4000 scans. In case of unclear assignment all
possible hydrogen and carbon atoms were stated. 19F NMR spectra
were recorded on a Bruker AV 300 (282 MHz) spectrometer. The
spectra were measured with standard number of scans. Mass spec-
© Georg Thieme Verlag Stuttgart · New York
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210
V. O. Iaroshenko et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 1.33 (s, 9 H, t-Bu), 7.14–7.21 (m,
1 H, CHAr), 7.24–7.29 (m, 1 H, CHAr), 7.43 (dt, 3J = 8.6 Hz, 4J = 1.9
13C NMR (62.9 MHz, CDCl3): δ = 21.7 (Me), 88.2, 94.0 (C), 105.2
(t, J = 22.6 Hz, CH), 111.86 (dd, J = 22.0 Hz, J = 3.9 Hz, CH),
116.8, 122.4–122.6 (C), 129.5, 133.2 (CH), 133.7 (dd, J = 11.2 Hz,
J = 1.8 Hz, CH), 141.8 (C), 160.9 (d, J = 12.4 Hz, C), 164.2 (d,
J = 12.0 Hz, C), 165.1 (d, J = 12.8 Hz, C), 168.3 (d, J = 12.5 Hz,
CH), 172.7 (C).
3
Hz, 2 H, CHAr), 7.53–7.58 (m, 1 H, CHAr), 7.60 (dt, J = 8.6 Hz,
3
4
4J = 1.9 Hz, 2 H, CHAr), 8.10 (dt, J = 7.6 Hz, J = 1.9 Hz, 1 H,
CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 31.0 (t-Bu), 35.1 (C), 88.4 (C),
4
4
99.8 (t, J = 3.2 Hz, C), 117.0 (d, J = 6.7 Hz, CHAr), 117.3 (C),
19F NMR (282 MHz, CDCl3): δ = –106.0 (d, 3J = 13.1 Hz), –99.7 (d,
4
124.1 (d, J = 3.8 Hz, CH), 125.7, 131.8, 133.1 (CH), 135.4 (d,
3J = 13.1 Hz).
3J = 8.7 Hz, CH), 154.7, 160.0, 164.2, 174.3 (C).
19F NMR (282 MHz, CDCl3): δ = –111.0.
MS (GC, 70 eV): m/z (%) = 256 (93) [M+], 228 (95), 207 (16), 143
(100), 113 (23), 63 (28).
MS (GC, 70 eV): m/z (%) = 280 (30) [M+], 265 (100), 123 (17).
HRMS (EI): m/z [M + H]+ calcd for C16H11F2O: 257.07725; found:
257.07696.
HRMS (EI): m/z [M+] calcd for C19H17FO: 280.12579; found:
280.126387.
1-(2,6-Difluorophenyl)-3-phenylprop-2-yn-1-one (3f)
Yellow oil; yield: 3.39 g (70%).
3-(4-tert-Butylphenyl)-1-(2,5-difluorophenyl)prop-2-yn-1-one
(3c)
IR (ATR): 3060 (w), 2193 (s), 1641 (s), 1619 (s), 1489 (w), 1464
(s), 1302 (m), 1288 (m), 1236 (m), 1202 (m), 1068 (w), 1031 (m),
1002 (s), 990 (s), 818 (w), 793 (s), 754 (s), 685 (s), 591 (w), 571 (s),
535 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.79–6.84 (m, 2 H, CHAr), 7.18–
7.33 (m, 4 H, CHAr), 7.41–7.44 (m, 2 H, CHAr).
Yellow oil; yield: 5.00 g (84%).
IR (ATR): 2962 (w), 2186 (s), 1634 (m), 1589 (m), 1487 (s), 1419
(s), 1364 (s), 1312 (m), 1291 (m), 1252 (s), 1190 (m), 1154 (s), 1101
(m), 1037 (m), 1010 (m), 914 (m), 884 (w), 823 (s), 778 (m), 753
(s), 702 (m), 654 (m), 564 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.22 (s, 9 H, t-Bu), 7.01–7.08 (m,
13C NMR (62.9 MHz, CDCl3): δ = 89.0 (C), 93.2 (t, 4J = 2.0 Hz, C),
3
4
4
1 H, CHAr), 7.11–7.19 (m, 1 H, CHAr), 7.33 (d, J = 8.7 Hz, 2 H,
112.0 (d, J = 3.1 Hz, CH), 112.3 (d, J = 3.1 Hz, CH), 117.2 (t,
3J = 15.0 Hz, C), 119.4 (C), 128.5, 131.0, 133.0 (C), 133.7 (t,
3J = 10.3 Hz, CH), 158.5 (d, 4J = 5.6 Hz, C), 162.6 (d, 4J = 5.6 Hz,
C), 171.1 (C).
19F NMR (282 MHz, CDCl3): δ = –111.0.
MS (GC, 70 eV): m/z (%) = 242 (44) [M+], 214 (100), 129 (59).
CHAr), 7.50 (d, 3J = 8.7 Hz, 2 H, CHAr), 7.62–7.68 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 30.9 (Me), 35.1, 88.1, 94.6,
3
4
116.7 (C), 117.4 (dd, J = 24.9 Hz, J = 1.2 Hz, CH), 120.1 (dd,
1J = 221.8 Hz, 2J = 9.5 Hz, CH), 120.5 (dd, 1J = 221.8 Hz, 2J = 9.5
Hz, CH), 125.7 (CH), 126.5 (dd, J = 221.8 Hz, J = 8.2 Hz, CH),
126.5 (C), 133.2 (CH), 155.0, 156.1 (C), 160.1 (d, 4J = 4.6 Hz, C),
172.7 (C).
3
4
HRMS (EI): m/z [M+] calcd for C15H8F2O: 242.05377; found:
242.053779.
19F NMR (282 MHz, CDCl3): δ = –117.3 (d, 3J = 18.2 Hz), –117.0
(d, 3J = 18.2 Hz).
1-(2,6-Difluorophenyl)-3-(4-tolyl)prop-2-yn-1-one (3g)
Yellow oil; yield: 3.74 g (73%).
MS (GC, 70 eV): m/z (%) = 298 (26) [M+], 283 (100), 141 (19).
HRMS (EI): m/z [M+] calcd for C19H16F2O: 298.11637; found:
298.116143.
IR (ATR): 3032 (w), 2189 (s), 1643 (s), 1619 (s), 1508 (m), 1302
(s), 1236 (s), 1202 (m), 1177 (m), 1067 (w), 1027 (m), 994 (s), 815
(s), 793 (s), 755 (w), 725 (m), 687 (w), 572 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.18 (s, 3 H, Me), 6.75–6.80 (m,
1-(2,5-Difluorophenyl)-3-(4-tolyl)prop-2-yn-1-one (3d)
Yellow oil; yield: 4.66 g (91%); mp 69 °C.
2 H, CHAr), 6.97–7.05 (m, 2 H, CHAr), 7.20–7.32 (m, 3 H, CHAr).
IR (ATR): 2922 (w), 2187 (s), 1615 (m), 1582 (m), 1483 (m), 1420
(s), 1316 (m), 1925 (m), 1246 (s), 1191 (m), 1150 (s), 1108 (m),
1039 (m), 911 (m), 895 (m), 812 (s), 768 (m), 737 (s), 658 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H, Me), 7.11–7.29 (m,
13C NMR (62.9 MHz, CDCl3): δ = 21.8 (Me), 89.2, 94.2 (C), 112.0
(d, J = 3.1 Hz, CH), 112.4 (d, J = 3.1 Hz, CH), 116.7 (C), 117.7 (t,
J = 15.0 Hz, C), 129.4 (C), 132.0 (d, J = 3.1 Hz, C), 133.4 (CH),
142.0 (C), 158.8 (d, J = 5.7 Hz, C), 162.9 (d, J = 5.7 Hz, C), 171.3
(C).
4 H, CHAr), 7.54–7.57 (m, 2 H, CHAr), 7.72–7.78 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 21.8 (Me), 88.2, 94.7, 116.7 (C),
117.2, 117.6 (CH), 120.1 (dd, J = 223.6 Hz, J = 6.9 Hz, CH),
120.5 (dd, 1J = 223.6 Hz, 2J = 6.9 Hz, CH), 126.5–126.7 (C), 129.5,
133.4 (CH), 142.0, 156.1–156.3, 160.2, 172.8 (C).
19F NMR (282 MHz, CDCl3): δ = –111.0.
MS (GC, 70 eV): m/z (%) = 256 (81) [M+], 228 (88), 143 (100).
HRMS (EI): m/z [M + H]+ calcd for C16H11F2O: 257.07725; found:
257.07721.
1
2
19F NMR (282 MHz, CDCl3): δ = –117.3 (d, 3J = 18.3 Hz), –117.1
(d, 3J = 18.3 Hz).
3-(4-tert-Butylphenyl)-1-(2,6-difluorophenyl)prop-2-yn-1-one
MS (GC, 70 eV): m/z (%) = 256 (67) [M+], 228 (48), 207 (13), 143
(100), 63 (22).
(3h)
Yellow oil; yield: 4.77 g (80%).
HRMS (ESI): m/z [M + H]+ calcd for C16H11F2O: 257.07725; found:
257.07736.
IR (ATR): 2962 (w), 2191 (s), 1644 (s), 1619 (s), 1504 (w), 1465
(s), 1364 (w), 1302 (s), 1237 (s), 1205 (m), 1109 (w), 1067 (w),
1026 (s), 994 (s), 835 (s), 793 (s), 688 (m), 564 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 9 H, t-Bu), 6.95–7.01 (m,
2 H, CHAr), 7.39–7.48 (m, 3 H, CHAr), 7.54–7.58 (m, 2 H, CHAr).
1-(2,4-Difluorophenyl)-3-(4-tolyl)prop-2-yn-1-one (3e)
Yellow oil; yield: 4.97 g (97%).
IR (ATR): 2198 (s), 1629 (m), 1601 (s), 1495 (m), 1426 (m), 1307
(s), 1267 (s), 1231 (m), 1198 (m), 1179 (m), 1104 (s), 1028 (m), 967
(m), 852 (s), 811 (s), 746 (s), 666 (m), 594 (s).
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H, Me), 7.11–7.29 (m,
13C NMR (62.9 MHz, CDCl3): δ = 31.0 (t-Bu), 35.1, 89.2, 94.2 (C),
112.1–112.5 (m, CH), 116.7 (C), 125.7, 133.2 (CH), 133.5 (t,
J = 12.6 Hz, CH), 155.0 (C), 158.8 (d, J = 5.6 Hz, C), 162.9 (d,
J = 5.7 Hz, C), 171.4 (C).
4 H, CHAr), 7.54–7.57 (m, 2 H, CHAr), 7.72–7.78 (m, 1 H, CHAr).
19F NMR (282 MHz, CDCl3): δ = –111.0.
Synthesis 2013, 45, 205–218
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4-Quinolones by Domino Amination and Conjugate Addition Reactions
211
MS (GC, 70 eV): m/z (%) = 298 (30) [M+], 283 (100), 227(12), 141
(23).
2 H, CHAr), 7.15–7.20 (m, 5 H, CHAr), 7.41–7.51 (m, 4 H, CHAr),
7.66–7.79 (m, 2 H, CHAr), 8.55 (dd, 3J = 8.0 Hz, 4J = 1.2 Hz, 1 H,
CHAr).
HRMS (EI): m/z [M+] calcd for C19H16FO: 298.11637; found:
298.116627.
13C NMR (62.9 MHz, CDCl3): δ = 34.8, 49.4 (CH2), 112.8, 116.2,
123.8, 127.0, 128.3, 128.5, 128.7, 128.8, 129.4, 132.5 (CHAr),
135.7, 136.8, 140.4, 154.9, 177.1 (CAr).
MS (GC, 70 eV): m/z (%) = 325 (31) [M+], 234 (100), 132 (18).
HRMS (EI): m/z [M+] calcd for C23H19NO: 325.14612; found:
1-(2,6-Difluorophenyl)oct-2-yn-1-one (3i)
Yellow oil; yield: 3.30 g (70%).
IR (ATR): 2932 (w), 2862 (s), 2206 (m), 1650 (s), 1619 (s), 1466
(s), 1280 (m), 1252 (s), 1233 (s), 1121 (w), 1009 (s), 915 (w), 870
(w), 794 (s), 758 (w), 690 (w), 570 (m) cm–1.
325.14617.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3J = 7.2 Hz, 3 H,
CH3CH2), 1.28–1.45 (m, 4 H, 2 × CH2), 1.56–1.66 (m, 2 H, CH2),
2.42 (t, J = 7.1 Hz, 2 H, CCH2), 6.94 (t, J = 8.4 Hz, 2 H, CHAr),
2-Phenyl-1-(3-phenylpropyl)quinolin-4(1H)-one (5b)
Yellow viscous oil; yield: 0.291 g (86%).
3
3
IR (ATR): 2937 (w), 1625 (s), 1594 (s), 1484 (m), 1463 (m), 1417
(s), 1299 (m), 1265 (m), 1212 (w), 1172 (m), 1078 (w), 1029 (w),
912 (w), 835 (s), 778 (m), 759 (s), 697 (s), 672 (s), 623 (m), 547 (m)
cm–1.
7.37–7.44 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 12.9 (CH3), 20.9, 27.5, 28.1, 47.1
3
(CH2), 89.2, 94.2, 116.7 (C), 117.7 (t, J = 15.0 Hz, C), 132.0 (d,
J = 3.1 Hz, C), 133.4 (CH), 142.0 (C), 158.8 (d, J = 5.7 Hz, CH),
162.9 (d, J = 5.7 Hz, CH), 171.3 (C).
19F NMR (282 MHz, CDCl3): δ = –111.4.
MS (GC, 70 eV): m/z (%) = 236 (1) [M+], 180 (17), 151 (21), 141
(100), 113 (17).
1H NMR (300 MHz, CDCl3): δ = 1.93–2.03 [m, 2 H, (CH2)3], 2.46
[t, 3J = 7.6 Hz, 2 H, (CH2)3], 3.96–4.01 [m, 2 H, (CH2)3], 6.23 (s, 1
H, CHAr), 6.97–7.00 (m, 2 H, CHAr), 7.14–7.48 (m, 10 H, CHAr),
7.56–7.62 (m, 1 H, CHAr), 8.49 (dd, 3J = 8.0 Hz, 4J = 1.5 Hz, 1 H,
CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 29.8, 32.6, 47.5 (CH2), 112.8,
116.1, 123.7, 126.3, 127.0, 128.1, 128.2, 128.5, 128.8, 129.5, 132.3
(CHAr), 135.8, 139.8, 140.5, 154.6, 177.0 (CAr).
HRMS (EI): m/z [M+] calcd for C14H14F2O: 236.10127; found:
236.10129.
MS (GC, 70 eV): m/z (%) = 339 (35) [M+], 375 (41), 361 (100), 243
(42), 91 (41).
HRMS (ESI): m/z [M+] calcd for C24H21NO: 339.16177; found:
339.16188.
3-(4-tert-Butylphenyl)-1-(pentafluorophenyl)prop-2-yn-1-one
(3j)
Yellow oil; yield: 5.28 g (75%); mp 127–129 °C.
IR (ATR): 2961 (w), 1524 (m), 1498 (s), 1392 (w), 1363 (m), 1267
(w), 1116 (m), 1060 (m), 1017 (w), 987 (s), 964 (s), 835 (s), 771
(w), 736 (w), 651 (w), 561 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.33 (s, 9 H, t-Bu), 7.33–7.52 (m,
1-(4-Methoxybenzyl)-2-phenylquinolin-4(1H)-one (5c)
Yellow solid, yield: 0.297 g (87%); mp 209–210 °C.
4 H, CHAr).
IR (ATR): 1623 (m), 1598 (s), 1514 (s), 1487 (s), 1429 (m), 1361
(w), 1313 (m), 1251 (s), 1176 (s), 1143 (m), 1034 (m), 960 (m), 833
(s), 806 (m), 760 (s), 703 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.74 (s, 3 H, OMe), 5.20 (s, 2 H,
CH2), 6.33 (s, 1 H, CHAr), 6.78–6.81 (m, 2 H, CHAr), 6.87–6.90 (m,
2 H, CHAr), 7.30–7.42 (m, 7 H, CHAr), 7.48–7.54 (m, 1 H, CHAr),
8.50 (dd, 3J = 8.7 Hz, 4J = 1.5 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 51.7 (OMe), 55.2 (CH2), 113.0,
114.4, 117.4, 123.7, 126.6, 126.7 (CHAr), 127.2 (CAr), 128.1, 128.6,
129.6, 132.3 (CHAr), 135.6, 141.1, 155.1, 159.0, 177.5 (CAr).
13C NMR (62.9 MHz, CDCl3): δ = 31.1 (t-Bu), 34.9 (d, 4J = 2.8 Hz,
C), 72.4 (m, C), 73.5, 81.5 (C), 100.6 (m, C), 101.9 (d, 4J = 3.4 Hz,
C), 118.7 (d, 3J = 20.1 Hz, C), 125.5 (d, 4J = 5.0 Hz, CH), 129.2 (m,
C), 131.7, 132.2 (CHAr), 135.6–135.8 (m, C), 139.0–139.7 (m, C),
143.4 (C), 144.9–145.2 (m, C), 152.9 (d, 3J = 36.6 Hz, C).
19F NMR (282 MHz, CDCl3): δ = –162.1, –153.3 (t, 3J = 19.5 Hz),
–136.3 to –136.2.
MS (GC, 70 eV): m/z (%) = 352 (100) [M+].
HRMS (EI): m/z [M+] calcd for C19H13F5O: 352.08866; found:
MS (GC, 70 eV): m/z (%) = 341 (7) [M+], 121 (100).
HRMS (EI): m/z [M+] calcd for C23H19NO2: 341.14103; found:
352.08870.
4-Quinolones 5, 6, 8, 9, 10, 11: General Procedure
341.14099.
The 1-(2-fluorophenyl)prop-2-yn-1-one derivative 3 (1 mmol),
amine 4 (2 mmol), and Li2CO3 (2 mmol, 0.148 g) were and dis-
solved in dry DMA (7 mL) in a pressure tube or a long Schlenk flask
under a flow of dry argon. The mixture was heated at 160 °C for 24–
30 h until the reaction was complete (TLC). The soln was evaporat-
ed under reduced pressure and the residue was purified by column
chromatography [silica gel, heptane–EtOAc (3:1)]. Synthesis of
compounds 10 generally took about 60 h. 4-Quinolones 5o, 5r, and
5s were subsequently used as the starting materials for the synthesis
of compounds 8h, 8i, and 9b, respectively. Compounds 6 were syn-
thesized analogously, but the reaction was conducted at 100 °C in
DMF. For further modifications, see Tables 1 and 2.
1-Pentyl-2-phenylquinolin-4(1H)-one (5d)
Yellow oil; yield: 0.244 g (84%).
IR (ATR): 2927 (m), 2863 (m), 1618 (s), 1595 (s), 1480 (s), 1422
(m), 1308 (m), 1267 (m), 1177 (m), 1080 (m), 963 (w), 835 (s), 756
(s), 703 (s), 668 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.73 [t, 3J = 7.0 Hz, 3 H,
CH3(CH2)3CH2], 1.03–1.13 [m, 4 H, CH3(CH2)3CH2], 1.57–1.67
[m, 2 H, CH3(CH2)3CH2], 3.95 [t, 3J = 8.0 Hz, 2 H, CH3(CH2)3CH2],
6.19 (s, 1 H, CHAr), 7.31–7.36 (m, 3 H, CHAr), 7.43–7.51 (m, 4 H,
CHAr), 7.61–7.67 (m, 1 H, CHAr), 8.46 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz,
1 H,CHAr).
13C NMR (75.5 MHz, CDCl3): δ = 12.9 (CH3), 20.9, 27.5, 28.1, 47.1
(CH2), 111.7, 115.3, 122.5, 125.9 (CHAr), 126.3 (CAr), 127.2, 127.7
(CHAr), 128.1 (CAr), 128.4, 131.2 (CHAr), 135.0, 139.6, 153.5, 176.3
(CAr).
2-Phenyl-1-(2-phenylethyl)quinolin-4(1H)-one (5a)
White solid, yield: 0.289 g (89%); mp 145–146 °C.
IR (ATR): 1616 (m), 1589 (s), 1553 (s), 1483 (m), 1416 (m), 1368
(w), 1311 (m), 1268 (m), 1174 (m), 1143 (m), 1074 (w), 1003 (w),
862 (w), 776 (m), 755 (s), 704 (s), 669 (m), 557 (m) cm–1.
MS (GC, 70 eV): m/z (%) = 291 (50) [M+], 234 (100), 132 (17).
HRMS (EI): m/z [M+] calcd for C20H21NO: 291.16177; found:
1H NMR (300 MHz, CDCl3): δ = 2.92 [t, 3J = 7.6 Hz, 2 H, (CH2)2],
4.28 [t, 3J = 7.6 Hz, 2 H, (CH2)2], 6.25 (s, 1 H, CHAr), 6.72–6.76 (m,
291.16171.
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V. O. Iaroshenko et al.
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1-Hexyl-2-phenylquinolin-4(1H)-one (5e)
13C NMR (62.9 MHz, CDCl3): δ = 31.1 (t-Bu), 34.6 (C), 112.7,
117.7 (CH), 122.9 (C), 124.1, 125.0, 126.4, 128.9, 131.6, 132.1,
132.8 (CH), 138.3, 152.2, 154.2, 172.7, 177.6, 186.6 (C).
MS (GC, 70 eV): m/z (%) = 433 (100) [M+], 431 (99), 416 (36), 388
(17), 309 (11), 207 (15).
Yellow oil; yield: 0.271 g (89%).
IR (ATR): 3044 (w), 2927 (m), 1617 (m), 1594 (s), 1570 (m), 1479
(s), 1421 (m), 1306 (m), 1266 (m), 1177 (m), 1138 (m), 1035 (w),
923 (w), 835 (s), 758 (s), 703 (s), 668 (m), 550 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.79 [t, 3J = 7.2 Hz,
CH3(CH2)4CH2, 3 H], 1.06–1.20 [m, 6 H, CH3(CH2)4CH2], 1.60–
1.68 [m, 2 H, CH3(CH2)4CH2], 4.00 [t, 3J = 8.0 Hz, 2 H,
CH3(CH2)4CH2], 6.27 (s, 1 H, CHAr), 7.36–7.42 (m, 3 H, CHAr),
7.46–7.54 (m, 3 H, CHAr), 7.66–7.71 (m, 1 H, CHAr), 8.51 (dd,
3J = 8.0 Hz, 4J = 1.6 Hz, 1 H, CHAr).
HRMS (EI): m/z [M+] calcd for C25H22BrNO: 431.08793; found:
431.087506.
2-(4-tert-Butylphenyl)-1-(3,5-dimethoxyphenyl)-6-fluoroquino-
lin-4(1H)-one (5i)
Yellow solid; yield: 0.332 g (77%); mp 121 °C.
13C NMR (75.5 MHz, CDCl3): δ = 13.8 (CH3), 22.2, 26.0, 28.6,
30.9, 48.2 (CH2), 112.7, 116.2, 123.6, 127.0 (CHAr), 127.2 (CAr),
128.3, 128.7, 129.4, 132.2 (CHAr), 136.0, 140.5, 154.7, 177.0 (CAr).
MS (GC, 70 eV): m/z (%) = 305 (56) [M+], 234 (100), 132 (17).
HRMS (EI): m/z [M+] calcd for C21H23NO: 305.17742; found:
IR (ATR): 2961 (w), 1611 (s), 1579 (s), 1506 (w), 1456 (s), 1427
(m), 1386 (m), 1290 (m), 1252 (m), 1193 (m), 1152 (s), 1057 (m),
1012 (w), 930 (m), 834 (s), 700 (m), 603 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.24 (s, 9 H, t-Bu), 3.67 (s, 6 H, 2
× OMe), 6.29 (q, 4J = 2.3 Hz, 2 H, CHAr), 6.38–6.40 (m, 2 H, CHAr),
7.04–7.24 (m, 6 H, CHAr), 8.10 (dd, 3J = 8.9 Hz, 4J = 3.0 Hz, 1 H,
CHAr).
305.17731.
13C NMR (62.9 MHz, CDCl3): δ = 31.1 (t-Bu), 34.6 (C), 55.6 (2 ×
1-(3,5-Dimethoxyphenyl)-2-phenylquinolin-4(1H)-one (5f)
2
Light-yellow solid; yield: 0.264 g (74%); mp 216–218 °C.
OMe), 101.1, 108.3 (CH), 110.3 (d, J = 22.4 Hz, CHAr), 111.8
(CHAr), 120.1–120.6 (m, CHAr), 124.8 (CHAr), 127.4 (d, 4J = 7.0
Hz, C), 128.6 (CHAr), 132.5, 138.8, 140.5, 152.0, 154.0, 157.2,
161.3, 177.0 (C).
IR (ATR): 3035 (w), 2197 (w), 1628 (m), 1590 (s), 1462 (s), 1417
(s), 1359 (m), 1314 (m), 1264 (m), 1205 (s), 1150 (s), 1053 (s), 927
(m), 891 (w), 830 (m), 773 (m), 754 (s), 712 (s), 639 (w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.66 (s, 6 H, 2 × OMe), 6.10 (s, 1
H, CHAr), 6.47 (t, 4J = 2.1 Hz, 1 H, CHAr), 6.64 (d, 4J = 2.4 Hz, 2 H,
CHAr), 6.99 (d, 3J = 8.6 Hz, 1 H, CHAr), 7.25–7.29 (m, 3 H, CHAr),
7.38–7.43 (m, 3 H, CHAr), 7.58–7.64 (m, 1 H, CHAr), 8.25 (dd,
3J = 7.8 Hz, 4J = 1.4 Hz, 1 H, CHAr).
19F NMR (282 MHz, CDCl3): δ = –117.8.
MS (GC, 70 eV): m/z (%) = 431 (100) [M+], 416 (42).
HRMS (ESI): m/z [M + H]+ calcd for C27H27FNO3: 432.19695;
found: 432.19788.
13C NMR (62.9 MHz, DMSO): δ = 55.5 (OMe), 100.8, 108.6,
111.2, 118.3, 123.6, 125.1 (CH), 125.4 (C), 127.6, 128.6, 129.0,
132.2 (CH), 133.0, 135.5, 140.3, 142.1, 153.8, 160.7, 176.0 (C).
2-(4-tert-Butylphenyl)-6-fluoro-1-(4-methoxyphenyl)quinolin-
4(1H)-one (5j)
White solid; yield: 0.313 g (78%); mp 185 °C.
IR (ATR): 2958 (w), 1609 (s), 1580 (m), 1505 (s), 1480 (s), 1391
(m), 1361 (m), 1294 (m), 1243 (s), 1173 (s), 1135 (m), 1084 (w),
1032 (m), 927 (m), 884 (m), 860 (w), 832 (s), 795 (s), 713 (w), 631
(m), 540 (s) cm–1.
MS (GC, 70 eV): m/z (%) = 357 (100) [M+], 329 (42).
HRMS (EI): m/z [M+] calcd for C23H19NO3: 357.13594; found:
357.136003.
1H NMR (300 MHz, CDCl3): δ = 1.23 (s, 9 H, t-Bu), 3.78 (s, 3 H,
OMe), 6.42 (s, 1 H, CHAr), 6.83–6.86 (m, 2 H, CHAr), 6.90–6.95 (m,
2 H, CHAr), 7.01–7.08 (m, 4 H, CHAr), 7.14–7.21 (m, 2 H, CHAr),
8.10 (dd, 3J = 8.9 Hz, 4J = 2.9 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 31.1 (t-Bu), 34.6 (C), 55.5
(OMe), 110.6 (d, J = 19.8 Hz, CH), 114.7, 120.1 (CH), 120.5 (d,
J = 7.4 Hz, CH), 124.8, 128.9, 130.8 (CH), 131.7, 132.5, 139.5,
151.8, 154.7, 157.2, 159.5, 161.2 (C).
19F NMR (282 MHz, CDCl3): δ = –117.8.
MS (GC, 70 eV): m/z (%) = 401 (100) [M+], 386 (29), 358 (13).
HRMS (EI): m/z [M+] calcd for C26H24FNO2: 401.17856; found:
401.179009.
2-(4-tert-Butylphenyl)-1-(4-chlorophenyl)quinolin-4(1H)-one
(5g)
Yellow oil; yield: 0.290 g (75%).
IR (ATR): 2962 (w), 1631 (s), 1603 (s), 1557 (w), 1505 (m), 1489
(s), 1408 (m), 1318 (m), 1269 (m), 1137 (w), 1081 (m), 1023 (m),
970 (w), 833 (s), 742 (s), 666 (m), 638 (m), 548 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.25 (s, 9 H, t-Bu), 6.42 (s, 1 H,
CHAr), 6.87 (d, 3J = 8.6 Hz, 1 H, CHAr), 7.04–7.11 (m, 4 H, CHAr),
7.20–7.22 (m, 2 H, CHAr), 7.32–7.50 (m, 4 H, CHAr), 8.50 (dd,
3J = 8.1 Hz, 4J = 1.3 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 31.1 (t-Bu), 34.6 (C), 112.8,
117.7, 123.9, 125.0, 126.4, 128.9, 129.8, 131.3, 131.9 (CH), 132.4,
134.8, 137.8, 142.5, 152.1, 153.9, 178.1 (C).
MS (GC, 70 eV): m/z (%) = 387 (100) [M+], 372 (46), 344 (20).
HRMS (EI): m/z [M+] calcd for C25H22ClNO: 387.13844; found:
6-Fluoro-1-hexyl-2-(4-tolyl)quinolin-4(1H)-one (5k)
White solid; yield: 0.286 g (85%); mp 181–182 °C.
IR (ATR): 3470 (m), 2928 (m), 1597 (s), 1564 (s), 1510 (m), 1471
(s), 1397 (m), 1299 (m), 1255 (w), 1205 (w), 1160 (m), 1115 (w),
1007 (w), 936 (m), 892 (m), 846 (s), 821 (s), 710 (m), 617 (m).
1H NMR (300 MHz, CDCl3): δ = 0.77 [t, 3J = 7.3 Hz, 3 H,
CH3(CH2)4CH2], 1.07–1.18 [m, 6 H, CH3(CH2)4CH2], 1.59–1.64
[m, 2 H, CH3(CH2)4 CH2], 2.42 (s, 3 H, Me), 3.99 [t, 3J = 8.2 Hz, 2
H, CH3(CH2)4CH2], 6.16 (s, 1 H, CHAr), 7.22–7.29 (m, 4 H, CHAr),
7.74–7.41 (m, 1 H, CHAr), 7.49–7.53 (m, 1 H, CHAr), 8.10 (dd,
3J = 9.0 Hz, 4J = 3.0 Hz, 1 H,CHAr).
387.138553.
2-(4-tert-Butylphenyl)-1-(4-bromophenyl)quinolin-4(1H)-one
(5h)
Beige solid; yield: 0.315 g (73%); mp 245–245 °C.
IR (ATR): 2962 (w), 1630 (s), 1602 (s), 1505 (w), 1486 (s), 1469
(m), 1408 (m), 1363 (w), 1318 (m), 1269 (m), 1137 (w), 1068 (w),
1020 (m), 670 (w), 876 (w), 832 (s), 744 (s), 730 (m), 666 (m), 637
(m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.25 (s, 9 H, t-Bu), 6.49 (s, 1 H,
CHAr), 6.88 (d, 3J = 8.9 Hz, 1 H, CHAr), 7.02–7.07 (m, 4 H, CHAr),
7.20–7.23 (m, 2 H, CHAr), 7.35–7.51 (m, 4 H, CHAr), 8.50 (dd,
3J = 7.9 Hz, 4J = 1.2 Hz, 1 H, CHAr).
13C NMR (75.5 MHz, CDCl3): δ = 13.8, 21.3 (Me), 22.3, 26.9, 28.6,
29.6, 48.4 (CH2), 111.4 (d, J = 20 Hz, CHAr), 112.2 (CHAr), 118.6
(d, J = 8 Hz, CHAr), 120.5 (d, J = 27 Hz, CHAr), 128.1 (CHAr),
Synthesis 2013, 45, 205–218
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4-Quinolones by Domino Amination and Conjugate Addition Reactions
213
128.8 (d, J = 35 Hz, CAr), 129.4 (CHAr), 132.9, 137.1, 139.6,
154.8, 157.0, 160.9, 176.3 (CAr).
138.7 (C), 144.2 (d, J = 11.5 Hz, C), 152.5, 154.9 (C), 164.7 (d,
J = 249.5 Hz, C), 177.1 (C).
19F NMR (282 MHz, CDCl3): δ = –118.8.
MS (GC, 70 eV): m/z (%) = 337 (52) [M+], 266 (100), 150 (18).
19F NMR (282 MHz, CDCl3): δ = –105.5.
MS (GC, 70 eV): m/z (%) = 385 (100) [M+], 370 (59).
HRMS (EI): m/z [M+] calcd for C22H24FNO: 337.18419; found:
HRMS (ESI): m/z [M + H]+ calcd for C26H25FNO: 386.19147;
337.18421.
found: 386.1918.
6-Fluoro-1-(2-phenylethyl)-2-(4-tolyl)quinolin-4(1H)-one (5l)
1-(3,5-Dimethylphenyl)-7-fluoro-2-(4-tolyl)quinolin-4(1H)-one
(5o)
Yellow oil; yield: 0.314 g (88%).
Yellow solid; yield: 0.282 g (79%); mp 271–273 °C.
IR (ATR): 1633 (m), 1613 (s), 1510 (m), 1479 (s), 1396 (m), 1350
(w), 1295 (m), 1203 (w), 1155 (m), 1063 (w), 1002 (w), 930 (m),
898 (m), 832 (s), 806 (m), 779 (m), 746 (m), 729 (m), 698 (m) cm–1.
IR (ATR): 2917 (w), 1633 (s), 1601 (s), 1511 (w), 1441 (s), 1386
(s), 1313 (m), 1261 (m), 1166 (m), 1125 (m), 1080 (w), 1021 (w),
951 (w), 848 (s), 819 (s), 763 (m), 709 (m), 640 (w), 596 (w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 6 H, 2 × Me), 2.25 (s, 3 H,
Me), 6.37 (s, 1 H, CHAr), 6.57 (dd, 3J = 11.3 Hz, 4J = 2.4 Hz, 1 H,
CHAr), 6.73 (s, 2 H, CHAr), 6.94–7.08 (m, 6 H, CHAr), 8.44–8.50 (m,
1 H, CHAr).
1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H, Me), 2.90 [t, 3J = 7.5
3
Hz, 2 H, (CH2)2], 4.28 [t, J = 7.5 Hz, 2 H, (CH2)2], 6.16 (s, 1 H,
CHAr), 6.73–6.76 (m, 2 H, CHAr), 7.03–7.06 (m, 2 H, CHAr), 7.15–
7.22 (m, 5 H, CHAr), 7.43–7.49 (m, 1 H, CHAr), 7.62–7.67 (m, 1 H,
CHAr), 8.18 (dd, 3J = 8.9 Hz, 4J = 3.1 Hz, 1 H, CHAr).
13C NMR (75.5 MHz, CDCl3): δ = 21.0, 21.2 (Me), 104.2 (d,
J = 27.1 Hz, CH), 112.4 (d, J = 23 Hz, CH), 112.6 (CH), 122.7 (C),
127.2, 128.5, 128.9 (CH), 129.1 (d, J = 10.6 Hz, CH), 130.7 (CH),
132.6 (C), 138.6 (d, J = 2.6 Hz, C), 139.5 (C), 144.1 (d, J = 11.3 Hz,
C), 154.7, 163.0, 166.3, 177.1 (C).
13C NMR (62.9 MHz, CDCl3): δ = 21.4 (Me), 34.5, 49.5 (CH2),
111.8 (d, J = 21.4 Hz, CHAr), 112.3 (CHAr), 118.5 (d, J = 7.6 Hz,
CHAr), 120.8 (d, J = 25.5 Hz, CHAr), 127.0, 128.1, 128.5, 128.8
(CHAr), 129.0 (d, J = 40 Hz, CAr), 132.7, 136.7, 137.0, 139.6,
155.0, 157.4, 160.7, 176.3 (CAr).
19F NMR (282 MHz, CDCl3): δ = –105.7.
19F NMR (282 MHz, CDCl3): δ = –117.8.
MS (GC, 70 eV): m/z (%) = 357 (100) [M+], 329 (91), 150 (13).
MS (GC, 70 eV): m/z (%) = 357 (1) [M+], 234 (100).
HRMS (ESI): m/z [M + H]+ calcd for C24H21FNO: 358.16017;
found: 358.16006.
HRMS (EI): m/z [M+] calcd for C24H20FNO: 357.15289; found:
357.15290.
1-(3,5-Dimethylphenyl)-5-fluoro-2-phenylquinolin-4(1H)-one
(5p)
Light-yellow solid; yield: 0.264 g (77%); mp 132 °C.
6-Fluoro-1-(3-phenylpropyl)-2-(4-tolyl)quinolin-4(1H)-one
(5m)
White solid; yield: 0.308 g (83%); mp 163–165 °C.
IR (ATR): 3047 (w), 1614 (s), 1471 (s), 1403 (s), 1307 (m), 1198
(w), 1120 (w), 1056 (m), 932 (w), 846 (M), 799 (m), 753 (s), 728
(m), 702 (s), 648 (m), 536 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.21 (s, 6 H, 2 × Me), 6.36 (s, 1 H,
CHAr), 6.69–6.72 (m, 3 H, CHAr), 6.91–6.98 (m, 2 H, CHAr), 7.12–
7.20 (m, 5 H, CHAr), 7.30–7.37 (m, 1 H, CHAr).
13C NMR (62.9 MHz, DMSO-d6): δ = 21.0 (Me), 110.1 (d, J = 17.4
Hz, CH), 114.1 (CH), 114.2 (d, J = 4.6 Hz, CH), 116.2 (d, J = 8.6
Hz, C), 127.3, 127.7, 128.6, 129.0, 130.5 (CH), 131.7 (d, J = 10.3
Hz, C), 135.2, 139.5 (C), 144.8 (d, J = 3.8 Hz, C), 153.4, 160.0,
163.5, 176.8 (C).
19F NMR (282 MHz, CDCl3): δ = –112.1.
MS (GC, 70 eV): m/z (%) = 343 (97) [M+], 315 (100), 299 (14).
HRMS (EI): m/z [M+] calcd for C23H18FNO: 343.13669; found:
343.137067.
IR (ATR): 2919 (w), 1634 (s), 1604 (s), 1576 (m), 1510 (m), 1470
(s), 1394 (m), 1295 (m), 1244 (w), 1201 (m), 1145 (s), 1055 (w),
975 (w), 930 (m), 888 (s), 833 (s), 822 (s), 746 (s), 700 (s), 561 (m)
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.84–1.92 [m, 2 H, (CH2)3], 2.35–
2.41 [m, 5 H, Me, (CH2)3], 3.88–3.94 [m, 2 H, (CH2)3], 6.08 (s, 1 H,
CHAr), 6.89–6.92 (m, 2 H, CHAr), 7.07–7.21 (m, 8 H, CHAr), 7.56–
7.62 (m, 1 H, CHAr), 8.02 (dd, 3J = 9.0 Hz, 4J = 2.6 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 20.4 (Me), 29.9, 31.5, 46.6
(CH2), 110.4 (d, J = 23 Hz, CHAr), 111.2 (CHAr), 117.4 (d, J = 7
Hz, CHAr), 119.1 (d, J = 25 Hz, CHAr), 125.3, 127.0, 127.2, 127.5
(CHAr), 127.8 (d, J = 27 Hz, CAr), 128.4 (CHAr), 131.7, 136.0
(CAr), 138.7 (d, J = 13 Hz, CHAr), 153.7, 156.0, 159.9, 175.3
(CAr).
19F NMR (282 MHz, CDCl3): δ = –118.1.
MS (GC, 70 eV): m/z (%) = 371 (77) [M+], 266 (100), 253 (19), 150
(20), 91 (27).
2-(4-tert-Butylphenyl)-5-fluoro-1-(3,5-dimethoxyphenyl)quino-
lin-4(1H)-one (5q)
Yellow solid; yield: 0.315 g (73%); mp 263–265 °C.
HRMS (EI): m/z [M+] calcd for C25H22FNO: 371.16854; found:
371.16856.
IR (ATR): 3003 (w), 1621 (s), 1558 (m), 1517 (m), 1504 (m), 1447
(s), 1365 (m), 1291 (m), 1257 (m), 1171 (m), 1122 (w), 1023 (w),
1000 (w), 842 (s), 742 (s), 660 (m), 565 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.21 (s, 9 H, t-Bu), 3.65 (s, 6 H, 2
× OMe), 6.01 (s, 1 H, CHAr), 6.47–6.48 (m, 1 H, CHAr), 6.62–6.63
(m, 2 H, CHAr), 6.78 (d, 3J = 9.1 Hz, 1 H, CHAr), 7.06–7.12 (m, 1 H,
CHAr), 7.28 (br s, 4 H, CHAr), 7.50–7.57 (m, 1 H, CHAr).
1-(4-tert-Butylphenyl)-7-fluoro-2-(4-tolyl)quinolin-4(1H)-one
(5n)
Yellow solid; yield: 0.289 g (75%); mp 218–220 °C.
IR (ATR): 2963 (w), 1639 (s), 1601 (s), 1510 (s), 1449 (s), 1392 (s),
1306 (s), 1263 (m), 1175 (m), 1124 (w), 1083 (w), 1027 (w), 986
(w), 841 (s), 814 (s), 754 (w), 660 (w), 634 (w), 571 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.28 (s, 9 H, t-Bu), 2.24 (s, 3 H,
Me), 6.43 (s, 1 H, CHAr), 6.59 (dd, 3J = 11.2 Hz, 4J = 2.2 Hz, 1 H,
CHAr), 6.94–7.10 (m, 7 H, CHAr), 7.32–7.37 (m, 2 H, CHAr), 8.46–
8.52 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 21.1 (Me), 31.2 (t-Bu), 34.8 (C),
104.2 (d, J = 27.6 Hz, CH), 112.5 (d, J = 22.3 Hz, CH), 112.7 (CH),
122.7 (C), 126.6, 128.5, 129.0, 129.1, 129.2 (CH), 132.5, 136.1,
13C NMR (62.9 MHz, CDCl3): δ = 28.9 (t-Bu), 32.3 (C), 52.9, 53.6
(OMe), 99.0, 106.5 (CH), 107.7 (d, J = 21.4 Hz, CH), 111.1, 112.4
(CH), 113.4 (C), 122.4, 126–9, 130.3 (CH), 138.6 (C), 142.3 (d,
J = 4.4 Hz, C), 149.1, 151.0, 157.0, 158.0, 160.5, 173.0 (C).
19F NMR (282 MHz, CDCl3): δ = –113.4.
MS (GC, 70 eV): m/z (%) = 431 (100) [M+], 416 (20), 388 (19).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 205–218

214
V. O. Iaroshenko et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C27H27FNO3: 432.19695;
found: 432.19743.
(2Z)-3-(4-tert-Butylphenyl)-1-(2,5-difluorophenyl)-3-[(2-
phenylethyl)amino]prop-2-en-1-one (6a)
Yellow oil; yield: 0.31 g (74%).
1-(3,5-Dimethylphenyl)-5-fluoro-2-(4-tolyl)quinolin-4(1H)-one
IR (ATR): 2948 (w), 1568 (m), 1538 (m), 1484 (m), 1456 (m), 1412
(m), 1364 (w), 1327 (m), 1288 (m), 1267 (m), 1246 (m), 1161 (m),
1143 (m), 1099 (m), 1065 (w), 1019 (w), 990 (w), 908 (w), 844 (m),
814 (s), 794 (m), 776 (m), 743 (s), 697 (s), 632 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 9 H, t-Bu), 2.85 (t, 3J = 6.9
Hz, 2 H, CH2), 3.48 (q, 3J = 6.9 Hz, 2 H, CH2), 5.64 (s, 1 H, CHC),
6.95–7.01 (m, 2 H, CHAr), 7.07–7.09 (m, 2 H, CHAr), 7.16–7.25 (m,
5 H, CHAr), 7.37–7.40 (m, 2 H, CHAr), 7.49–7.54 (m, 1 H, CHAr),
11.47 (s, 1 H, NH).
(5r)
Yellow oil; yield: 0.253 g (71%); mp 133–134 °C.
IR (ATR): 2917 (w), 1633 (s), 1614 (s), 1510 (w), 1471 (s), 1398
(s), 1305 (m), 1195 (w), 1116 (w), 1089 (w), 1056 (m), 933 (w), 830
(s), 795 (m), 752 (s), 726 (m), 666 (w), 602 (w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.22 (s, 6 H, 2 × Me), 2.24 (s, 3 H,
Me), 6.32 (s, 1 H, CHAr), 6.67–6.72 (m, 3 H, CHAr), 6.89–7.03 (m,
6 H, CHAr), 7.27–7.35 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 21.0, 21.1 (Me), 109.9 (d,
J = 21.5 Hz, CH), 114.2 (CH), 116.1 (d, J = 7.2 Hz, CH), 127.3,
128.4, 128.9, 130.5 (CH), 131.5 (d, J = 10.8 Hz, CH), 132.4, 138.5,
139.1, 139.4 (C), 144.8 (d, J = 3.8 Hz, C), 153.5, 160.0, 163.5,
176.8 (C).
19F NMR (282 MHz, CDCl3): δ = –112.3.
MS (GC, 70 eV): m/z (%) = 357 (79) [M+], 329 (100).
13C NMR (62.9 MHz, CDCl3): δ = 31.2 (Me), 34.7 (C), 37.3, 46.5
(CH2), 97.5 (d, 4J = 9.9 Hz, CHAr), 116.4 (dd, 3J = 24.8 Hz, 4J = 3.5
Hz, CH), 117.0–118.2 (m, 2 × C–F), 125.4, 126.6, 127.4, 128.5,
128.8 (CHAr), 130.3 (dd, J = 16.0 Hz, J = 6.5 Hz, CH), 132.0,
138.1, 152.9, 154.2, 156.7, 158.1, 160.5, 167.6 (C), 182.8 (d,
5J = 3.0 Hz, C).
3
4
19F NMR (282 MHz, CDCl3): δ = –118.8 (d, 3J = 18.6 Hz), –118.1
(d, 3J = 18.6 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C24H21FNO: 358.16017;
found: 358.16034.
MS (GC, 70 eV): m/z (%) = 419 (19) [M+], 328 (100), 272 (10), 141
(51).
1-(4-Ethylphenyl)-5-fluoro-2-(4-tolyl)quinolin-4(1H)-one (5s)
Yellow solid; yield: 0.250 g (70%); mp 250–251 °C.
HRMS (EI): m/z [M+] calcd for C27H27F2NO: 419.20552; found:
419.205681.
IR (ATR): 3057 (w), 2970 (w), 1633 (s), 1614 (s), 1511 (s), 1475
(s), 1407 (s), 1306 (m), 1253 (m), 1190 (w), 1122 (w), 1104 (w),
1037 (m), 920 (w), 857 (m), 831 (s), 789 (m), 747 (s), 650 (m), 598
(w) cm–1.
(2Z)-3-(1-Adamantylamino)-3-(4-tert-butylphenyl)-1-(2-fluoro-
phenyl)prop-2-en-1-one (6b)
Yellow solid; yield: 0.349 g (81%); mp 116–118 °C.
1H NMR (300 MHz, CDCl3): δ = 1.20 (t, 3J = 7.7 Hz, 3 H,
IR (ATR): 2904 (m), 1610 (m), 1583 (s), 1493 (m), 1477 (m), 1448
(m), 1398 (w), 1338 (s), 1299 (s), 1208 (m), 1150 (m), 1098 (m),
1086 (m), 1028 (m), 880 (w), 839 (m), 760 (s), 676 (w), 628 (w),
582 (m) cm–1.
3
CH3CH2), 2.24 (s, 3 H, Me), 2.62 (q, J = 7.7 Hz, 2 H, CH3CH2),
6.33 (s, 1 H, CHAr), 6.66 (d, 3J = 8.8 Hz, 1 H, CHAr), 6.90–7.02 (m,
7 H, CHAr), 7.14–7.17 (m, 2 H, CHAr), 7.27–7.35 (m, 1 H, CHAr).
1H NMR (300 MHz, CDCl3): δ = 1.29 (s, 9 H, t-Bu), 1.40–1.53 (m,
6 H, adamantyl), 1.73–1.74 (m, 6 H, adamantyl), 1.20 (br s, 3 H, ad-
amantyl), 6.92–6.99 (m, 1 H, CHAr), 7.09 (dt, 3J = 7.6 Hz, 4J = 1.1
13C NMR (75.5 MHz, CDCl3): δ = 15.1 (CH3CH2), 21.1 (Me), 28.4
(CH3CH2), 110.0 (d, J = 21.4 Hz, CH), 114.1 (d, J = 4.4 Hz, CH),
114.3, 128.5, 129.0, 129.6 (CH), 131.6 (d, J = 11.8 Hz, CH), 132.4,
136.9, 138.5 (C), 145.0 (d, J = 3.8 Hz, C), 145.3, 153.6, 160.0,
163.5 (C).
3
Hz, 1 H, CHAr), 7.20–7.32 (m, 6 H, CHAr), 7.76 (dt, J = 7.7 Hz,
4J = 1.9 Hz, 1 H, CHAr), 11.68 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 29.5 (CH), 31.3 (t-Bu), 34.7 (C),
35.9, 44.4 (CH2), 55.2 (CH), 99.5 (C), 116.0 (d, J = 24.6 Hz, CH),
123.9 (d, J = 3.5 Hz, CH), 124.5, 127.8 (CH), 129.1 (d, J = 13.7 Hz,
C), 130.4 (d, J = 3.0 Hz, CH), 131.4 (d, J = 8.8 Hz, CH), 134.8,
152.2, 158.3, 162.3, 167.3 (C), 183.8 (d, J = 3.1 Hz, C).
19F NMR (282 MHz, CDCl3): δ = –111.5.
MS (GC, 70 eV): m/z (%) = 357 (94) [M+], 329 (100), 314 (18).
HRMS (ESI): m/z [M + H]+ calcd for C24H21FNO: 358.16017;
found: 358.16061.
19F NMR (282 MHz, CDCl3): δ = –112.3.
MS (GC, 70 eV): m/z (%) = 431 (100) [M+], 374 (41), 336 (24), 308
5-Fluoro-1-(4-methoxyphenyl)-2-pentylquinolin-4(1H)-one (5t)
Yellow oil; yield: 0.244 g (72%).
(67), 252 (17), 123 (52).
HRMS (ESI): m/z [M + H]+ calcd for C29H34FNO: 432.26244;
found: 432.27007.
IR (ATR): 2923 (m), 1613 (s), 1507 (s), 1469 (s), 1408 (s), 1296
(m), 1235 (s), 1170 (m), 1107 (m), 1038 (s), 826 (m), 798 (m), 551
(m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.80 (t, 3J = 6.7 Hz, 3 H,
CH3CH2), 1.15–1.20 (m, 4 H, CH2), 1.47–1.53 (m, 2 H, CH2), 2.24
(t, 3J = 7.2 Hz, 2 H, CCH2), 3.91 (s, 3 H, OMe), 6.33 (s, 1 H, CHAr),
6.46 (d, 3J = 8.5 Hz, 1 H, CHAr), 6.87–6.93 (m, 1 H, CHAr), 7.07–
7.18 (m, 4 H, CHAr), 7.23–7.31 (m, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.8 (CH3CH2), 22.3, 27.9, 31.2,
33.5 (CH2), 55.7 (OMe), 109.9 (d, J = 23 Hz, CHAr), 111.7
(CHAr), 113.8 (d, J = 5 Hz, CHAr), 115.5, 130.1 (CHAr), 131.2–
131.5 (m, CHAr), 145.5, 154.9, 159.7, 160.3, 162.9, 163.7, 176.9
(CAr).
2-(4-tert-Butylphenyl)-1-(3-phenylpropyl)-5-[(3-phenylpro-
pyl)amino]quinolin-4(1H)-one (8a)
Yellow solid; yield: 0.433 g (82%); mp 215–216 °C.
IR (ATR): 2951 (w), 1617 (s), 1520 (m), 1450 (s), 1386 (w), 1264
(s), 1167 (s), 1121 (w), 1015 (w), 909 (w), 840 (m), 740 (s), 697 (s),
563 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H, t-Bu), 1.97–2.12 (m,
4 H, CH2), 2.45 (t, 3J = 7.5 Hz, 2 H, CH2), 2.81 (t, 3J = 7.5 Hz, 2 H,
CH2), 3.22 (t, 3J = 6.4 Hz, 2 H, CH2), 3.91 (t, 3J = 8.0 Hz, 2 H, CH2),
6.07 (s, 1 H, CHAr), 6.29–6.36 (m, 2 H, CHAr), 7.00–7.02 (m, 2 H,
CHAr), 7.16–7.31 (m, 11 H, CHAr), 7.44–7.47 (m, 2 H, CHAr), 10.47
(s, 1 H, NH).
19F NMR (282 MHz, CDCl3): δ = –112.2.
MS (GC, 70 eV): m/z (%) = 339 (22) [M+], 296 (17), 283 (100), 268
13C NMR (62.9 MHz, CDCl3): δ = 29.3, 30.2 (CH2), 31.2 (t-Bu),
32.6, 33.3 (CH2), 34.7 (C), 42.0, 48.0 (CH2), 100.2, 101.9, 112.5
(CHAr), 113.2 (C), 125.5, 125.7, 126.1, 127.9, 128.1, 128.3, 128.4,
(13), 121 (29).
HRMS (EI): m/z [M+] calcd for C22H22FNO2: 339.16291; found:
339.162750.
Synthesis 2013, 45, 205–218
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-Quinolones by Domino Amination and Conjugate Addition Reactions
215
128.5 (CHAr), 132.9 (C), 133.3 (CHAr), 140.2, 141.7, 143.2, 152.1,
152.3, 153.0, 180.8 (C).
MS (GC, 70 eV): m/z (%) = 528 (33) [M+], 437 (42), 423 (100), 305
MS (GC, 70 eV): m/z (%) = 578 (3) [M+], 427 (100), 165 (85).
HRMS (ESI): m/z [M + H]+ calcd for C36H39N2O5: 579.28535;
found: 579.2862.
(17), 91 (50).
1-[(1R)-1-Phenylethyl]-5-{[(1R)-1-phenylethyl]amino}-2-(4-tol-
yl)quinolin-4(1H)-one (8e)
Yellow solid; yield: 0.183 g (40%); mp 123–125 °C.
HRMS (ESI): m/z [M + H]+ calcd for C37H41N2O: 529.32134;
found: 529.32191.
IR (ATR): 2966 (w), 1616 (s), 1519 (m), 1505 (s), 1445 (s), 1377
(m), 1339 (w), 1267 (m), 1216 (m), 1159 (s), 1019 (w), 827 (m), 744
(m), 697 (s) cm–1.
2-(4-tert-Butylphenyl)-1-(4-methoxybenzyl)-5-[(4-methoxyben-
zyl)amino]quinolin-4(1H)-one (8b)
Yellow solid; yield: 0.452 g (85%); mp 192–193 °C.
IR (ATR): 2955 (w), 1614 (s), 1504 (s), 1447 (s), 1360 (w), 1244
(s), 1170 (s), 1110 (m), 1030 (m), 925 (w), 814 (m), 740 (m), 676
(m), 561 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 9 H, t-Bu), 3.76 (s, 3 H,
OMe), 3.78 (s, 3 H, OMe), 4.40 (s, 2 H, CH2), 5.12 (s, 2 H, CH2),
6.23–6.38 (m, 3 H, CHAr), 6.79–6.93 (m, 5 H, CHAr), 7.15–7.25 (m,
4 H, CHAr), 7.30–7.37 (m, 4 H, CHAr), 10.76 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 31.2 (t-Bu), 34.8 (C), 46.6, 52.4
(CH2), 55.2, 55.3 (OMe), 102.4, 103.1 (CHAr), 112.6 (C), 113.2,
114.0, 114.2 (CHAr), 125.5, 126.8, 127.9, 128.3 (CHAr), 128.6,
130.9, 132.6 (C), 133.4 (CHAr), 143.6, 151.5, 152.7, 154.0, 158.6,
158.8, 180.8 (C).
1H NMR (300 MHz, CDCl3): δ = 1.54 (d, 3J = 6.7 Hz, 3 H,
CHCH3), 1.78 (d, 3J = 6.7 Hz, 3 H, CHCH3), 2.30 (s, 3 H, Me), 4.43
3
(q, J = 6.7 Hz, 1 H, CHCH3), 5.68 (q, 3J = 6.7 Hz, 1 H, CHCH3),
5.94 (d, 3J = 8.5 Hz, 1 H, CHAr), 6.07 (d, 3J = 8.5 Hz, 1 H, CHAr),
6.11 (s, 1 H, CHAr), 6.80 (t, 3J = 8.5 Hz, 1 H, CHAr), 7.07–7.34 (m,
14 H, CHAr), 10.81 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 17.3, 21.3, 25.0 (Me), 53.1, 58.9
(CH), 103.5, 105.3, 113.5, 125.1, 126.0, 126.7, 127.0, 127.5, 128.5,
128.7, 129.5, 132.0 (CH), 133.6, 139.5, 140.5, 141.8, 145.2, 150.9,
154.2, 181.0 (C).
MS (GC, 70 eV): m/z (%) = 458 (19) [M+], 443 (22), 353 (100), 207
(28), 105 (19).
MS (GC, 70 eV): m/z (%) = 532 (8) [M+], 411 (47), 121 (100).
HRMS (EI): m/z [M+] calcd for C35H36N2O3: 532.27204; found:
HRMS (EI): m/z [M+] calcd for C32H30N2O: 458.23527; found:
458.235207.
532.272902.
1-(4-Ethylphenyl)-5-[(4-ethylphenyl)amino]-2-(4-tolyl)quino-
lin-4(1H)-one (8f)
2-(4-tert-Butylphenyl)-1-(2-phenylethyl)-5-[(2-phenyl-
ethyl)amino]quinolin-4(1H)-one (8c)
Yellow solid; yield: 0.465 g (93%); mp 185–187 °C.
Yellow solid; yield: 0.362 g (79%); mp 174–175 °C.
IR (ATR): 2960 (w), 1623 (m), 1591 (s), 1564 (m), 1504 (m), 1441
(s), 1376 (w), 1342 (w), 1274 (s), 1176 (m), 1112 (w), 1038 (w),
1018 (w), 844 (s), 819 (s), 751 (m), 721 (m), 636 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.11–1.20 (m, 6 H, 2 × CH3CH2),
2.17 (s, 3 H, Me), 2.51–2.61 (m, 4 H, 2 × CH3CH2), 5.91 (dd,
3J = 8.4 Hz, 4J = 0.8 Hz, 1 H, CHAr), 6.22 (s, 1 H, CHAr), 6.84–6.95
(m, 7 H, CHAr), 7.00–7.12 (m, 5 H, CHAr), 7.18–7.21 (m, 2 H,
CHAr), 11.99 (s, 1 H, NH).
13C NMR (75.5 MHz, CDCl3): δ = 15.2, 15.7 (2 × CH3CH2), 21.2
(Me), 28.3, 28.4 (2 × CH3CH2), 104.5, 104.9 (CHAr), 112.7 (CAr),
128.5, 128.6, 128.8, 129.0, 129.7, 132.5 (CHAr), 132.7, 137.4,
138.4, 138.7, 139.5, 144.9, 145.6, 148.9, 153.2, 181.4 (CAr).
IR (ATR): 2962 (w), 1635 (m), 1614 (m), 1585 (m), 1464 (m), 1401
(m), 1328 (w), 1257 (w), 1197 (m), 1153 (s), 1122 (m), 1057 (m),
837 (s), 794 (w), 752 (m), 711 (m), 664 (m), 583 (m) cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.35 (s, 9 H, t-Bu), 2.80–2.85
(m, 2 H, CH2), 2.94 (t, 3J = 7.0 Hz, 2 H, CH2), 3.37–3.46 (m, 2 H,
3
3
CH2), 4.07 (t, J = 8.1 Hz, 2 H, CH2), 6.47 (d, J = 8.5 Hz, 1 H,
CHAr), 6.71–6.74 (m, 2 H, CHAr), 6.90 (d, 3J = 8.5 Hz, 1 H, CHAr),
7.14–7.36 (m, 10 H, CHAr), 7.47–7.54 (m, 4 H, CHAr), 10.4 (t,
3J = 5.1 Hz, 1 H, NH).
13C NMR: Not recorded (insufficient solubility).
MS (GC, 70 eV): m/z (%) = 500 (3) [M+], 409 (100), 289 (14), 105
MS (GC, 70 eV): m/z (%) = 458 (100) [M+], 443 (38).
HRMS (ESI): m/z [M + H]+ calcd for C32H31N2O: 459.24309;
(35).
HRMS (ESI): m/z [M + H]+ calcd for C35H37N2O: 501.29004;
found: 501.29016.
found: 459.24294.
2-Pentyl-1-(2-phenylethyl)-5-[(2-phenylethyl)amino]quinolin-
4(1H)-one (8g)
Yellow oil; yield: 0.359 g (82%).
1-[2-(3,4-Dimethoxyphenyl)ethyl]-5-{[2-(3,4-dimethoxyphe-
nyl)ethyl]amino}-2-(4-tolyl)quinolin-4(1H)-one (8d)
Yellow solid; yield: 0.491 g (85%); mp 85–87 °C.
IR (ATR): 2943 (w), 2865 (w), 1626 (s), 1596 (s), 1554 (m), 1516
(m), 1453 (w), 1365 (w), 1264 (s), 1208 (w), 1172 (m), 1080 (w),
1029 (w), 854 (w), 828 (m), 750 (m), 738 (m), 696 (s), 628 (m)
cm–1.
IR (ATR): 2932 (w), 1616 (m), 1590 (m), 1505 (s), 1447 (m), 1257
(m), 1234 (s), 1138 (s), 1025 (s), 910 (w), 827 (m), 806 (m), 763
(m), 726 (m), 637 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.37 (s, 3 H, Me), 2.81 (t, 3J = 7.4
Hz, 2 H, CH2), 2.95–2.99 (m, 2 H, CH2), 3.40–3.46 (m, 2 H, CH2),
3.65 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 3.83 (s, 3 H, OMe), 3.87 (s,
3 H, OMe), 4.11 (t, 3J = 7.4 Hz, 2 H, CH2), 5.95 (s, 1 H, CHAr), 6.10
(d, 4J = 2.0 Hz, 1 H, CHAr), 6.32 (dd, 3J = 8.2 Hz, 4J = 1.7 Hz, 1 H,
CHAr), 6.38 (d, 3J = 8.3 Hz, 1 H, CHAr), 6.61–6.67 (m, 2 H, CHAr),
6.79–6.87 (m, 3 H, CHAr), 6.98 (d, 3J = 8.3 Hz, 2 H, CHAr), 7.19 (d,
3J = 7.4 Hz, 2 H, CHAr), 7.42 (t, 3J = 8.3 Hz, 1 H, CHAr), 10.51 (s, 1
H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 21.1 (Me), 33.6, 34.9, 44.9, 49.7
(CH2), 55.4, 55.6, 55.7, 55.8 (OMe), 110.3, 101.9, 111.1, 111.2,
111.4, 112.0 (CH), 112.5 (C), 113.0, 120.5, 128.2, 128.9 (CH),
129.4, 132.2, 132.9 (C), 133.3 (CH), 138.8, 143.0, 147.4, 147.7,
148.7, 148.8, 151.9, 152.9, 180.7.
1H NMR (300 MHz, CDCl3): δ = 0.78–0.83 [m,
3 H,
CH2(CH2)3CH3], 1.17–1.26 [m, 4 H, CH2(CH2)3CH3], 1.46–1.51
[m, 2 H, CH2(CH2)3CH3], 2.29 [t, 3J = 6.5 Hz, 2 H, CH2(CH2)3CH3],
2.92–2.97 (m, 4 H, CH2CH2), 3.36 [t, 3J = 7.3 Hz, 2 H, CH2CH2],
3
4.13 (t, J = 7.3 Hz, 2 H, CH2CH2), 5.92 (s, 1 H, CHAr), 6.28 (d,
3J = 8.7 Hz, 1 H, CHAr), 6.53 (d, 3J = 8.7 Hz, 1 H, CHAr), 7.04–7.34
(m, 11 H, CHAr), 10.44 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 13.8 (CH3CH2), 22.3, 28.2, 31.3,
33.3, 34.4, 35.4, 44.8, 47.5 (CH2), 99.8, 101.7, 111.4 (CHAr), 112.2
(CAr), 126.2, 127.0, 128.4, 128.6, 128.7, 128.9, 133.2 (CHAr), 137.5,
139.6, 143.4, 151.9, 152.6, 181.2 (CAr).
MS (GC, 70 eV): m/z (%) = 438 (4) [M+], 347 (100), 105 (42).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 205–218

216
V. O. Iaroshenko et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C30H35N2O: 439.27439;
found: 439.27482.
1-(4-Ethylphenyl)-5-[(2-phenylethyl)amino]-2-(4-tolyl)quino-
lin-4(1H)-one (8k)
Yellow oil; yield: 0.385 g (84%).
2-Pentyl-1-(3-phenylpropyl)-5-[(3-phenylpropyl)amino]quino-
lin-4(1H)-one (8h)
IR (ATR): 3214 (w), 2962 (w), 2865 (w), 1619 (m), 1504 (s), 1344
(w), 1267 (s), 1183 (m), 1021 (m), 851 (m), 816 (m), 740 (m), 698
(s), 565 (m) cm–1.
Yellow oil; yield: 0.245 g (75%).
IR (ATR): 2927 (w), 2857 (w), 1616 (s), 1594 (s), 1557 (m), 1518
(s), 1451 (s), 1370 (w), 1267 (s), 1170 (s), 1029 (w), 910 (w), 837
(w), 739 (s), 697 (s), 620 (m) cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 3J = 7.6 Hz, 3 H,
3
CH3CH2), 2.24 (s, 3 H, Me), 2.61 (q, J = 7.6 Hz, 2 H, CH3CH2),
3.05 (t, 3J = 7.3 Hz, 2 H, CH2CH2), 3.47 (t, 3J = 7.3 Hz, 2 H,
CH2CH2), 5.87 (d, 3J = 8.4 Hz, 1 H, CHAr), 6.23 (s, 1 H, CHAr), 6.34
1H NMR (300 MHz, CDCl3): δ = 0.88–0.93 [m,
3 H,
3
CH2(CH2)3CH3], 1.26–1.29 [m, 4 H, CH2(CH2)3CH3], 1.49–1.59
[m, 2 H, CH2(CH2)3CH3], 2.00–2.09 [m, 4 H, CH2(CH2)3CH3,
(CH2)3], 2.38–2.43 [m, 2 H, (CH2)3], 2.74–2.83 [m, 4 H, (CH2)3],
3.19 [t, 3J = 6.6 Hz, 2 H, (CH2)3], 3.95 [m, 2 H, (CH2)3], 6.03 (s, 1
H, CHAr), 6.25 (d, 3J = 8.2 Hz, 1 H, CHAr), 6.33 (d, 3J = 8.6 Hz, 1 H,
CHAr), 7.16–7.37 (m, 11 H, CHAr), 10.47 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 13.8 (CH3CH2), 22.3, 28.5, 29.4,
30.3, 31.3, 32.7, 33.2, 33.3, 42.0, 45.6 (CH2), 99.5, 101.5, 111.3
(CHAr), 112.1 (CAr), 125.7, 126.5, 128.2, 128.3, 128.5, 128.6, 133.0
(CHAr), 140.1, 141.7, 143.6, 152.0, 152.5, 181.2 (CAr).
(d, J = 8.0 Hz, 1 H, CHAr), 6.92–7.00 (m, 6 H, CHAr), 7.11–7.23
(m, 4 H, CHAr), 7.30–7.33 (m, 4 H, CHAr), 10.39 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 15.2 (CH3CH2), 21.2 (Me), 28.4,
35.4, 44.9 (CH2), 102.0, 103.0, 111.7 (CHAr), 112.8 (CAr), 126.3,
128.4, 128.5, 128.7, 128.8, 129.1, 129.7 (CHAr), 132.9, 137.5,
138.2, 139.7, 144.7, 145.6, 151.2, 152.7, 181.4 (CAr).
MS (GC, 70 eV): m/z (%) = 458 (3) [M+], 367 (100).
HRMS (ESI): m/z [M + H]+ calcd for C32H31N2O: 459.24309;
found: 459.24349.
MS (GC, 70 eV): m/z (%) = 466 (35) [M+], 375 (41), 361 (100), 243
(42), 91 (41).
HRMS (ESI): m/z [M + H]+ calcd for C32H39N2O: 467.30569;
1-[(1R)-1-Phenylethyl]-7-{[(1R)-1-phenylethyl]amino}-2-(4-tol-
yl)quinolin-4(1H)-one (9a)
Yellow oil; yield: 0.151 g (33%).
found: 467.30601.
IR (ATR): 3312 (w), 2969 (w), 1621 (w), 1575 (s), 1556 (s), 1488
(m), 1447 (m), 1318 (s), 1238 (s), 1205 (m), 1106 (s), 975 (w), 908
(w), 823 (m), 783 (m), 759 (m), 696 (s) cm–1.
1-(4-Methoxyphenyl)-5-[(4-methoxyphenyl)amino]-2-pentyl-
quinolin-4(1H)-one (8i)
Yellow oil; yield: 0.248 g (80%).
1H NMR (300 MHz, CDCl3): δ = 1.43 (t, 3J = 6.3 Hz, 6 H, CHCH3),
2.27 (s, 3 H, Me), 4.38–4.55 (m, 2 H, CHCH3), 5.63 (d, 4J = 1.7 Hz,
IR (ATR): 2928 (w), 1624 (s), 1601 (s), 1452 (s), 1263 (s), 1207 (s),
1123 (m), 1109 (s), 883 (m), 867 (s), 787 (m), 704 (w), 661 (s) cm–1.
3
4
1 H, CHAr), 5.99 (dd, J = 14.2 Hz, J = 2.2 Hz, 1 H, CHAr), 6.26
3
4
(dd, J = 8.7 Hz, J = 2.2 Hz, 1 H, CHAr), 7.04–7.24 (m, 14 H,
CHAr), 7.64 (t, 3J = 8.7 Hz, 1 H, CHAr), 11.58 (d, 3J = 9.5 Hz, 1 H,
NH).
1H NMR (300 MHz, CDCl3): δ = 0.75 (t, 3J = 7.0 Hz, 3 H,
CH3CH2), 1.09–1.18 (m, 4 H, CH2), 1.40–1.45 (m, 2 H, CH2), 2.15
(t, 3J = 7.7 Hz, 2 H, CCH2), 3.73 (s, 3 H, OMe), 3.83 (s, 3 H, OMe),
5.67 (dd, 3J = 8.4 Hz, 4J = 0.8 Hz, 1 H, CHAr), 6.13 (s, 1 H, CHAr),
6.60 (dd, 3J = 8.3 Hz, 4J = 0.8 Hz, 1 H, CHAr), 6.81–6.85 (m, 2 H,
CHAr), 6.92–7.01 (m, 3 H, CHAr), 7.05–7.09 (m, 2 H, CHAr), 7.15–
7.16 (m, 2 H, CHAr), 11.80 (s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 13.8 (CH3CH2), 22.3, 27.9, 31.2,
33.55 (CH2), 55.5, 55.6 (2 × OMe), 103.7, 104.3, 110.2 (CHAr),
111.7 (CAr), 114.5, 115.3, 125.7, 130.2, 131.9, 132.2 (CHAr), 134.0
(CAr), 146.1, 150.0, 154.0, 156.3, 159.9, 181.7 (CAr).
13C NMR (62.9 MHz, CDCl3): δ = 21.3, 24.5, 24.9 (Me), 53.2, 54.0
(CH), 98.0 (d, J = 10.0 Hz, CH), 99.4 (d, J = 30.3 Hz, CH), 109.3
(C), 117.3 (d, J = 11.3 Hz, CH), 125.7, 126.7, 127.2, 127.7, 128.5,
128.7, 128.8 (CH), 131.6 (d, J = 5.1 Hz, CH), 131.7 (d, J = 11.4 Hz,
CH), 133.2, 139.2, 144.0, 144.5 (C), 150.9 (d, J = 10.7 Hz, C),
160.4, 162.4 (d, J = 249.3 Hz, C), 184.8 (C).
MS (GC, 70 eV): m/z (%) = 458 (19) [M+], 353 (100).
HRMS (EI): m/z [M+] calcd for C32H30N2O: 458.59341; found:
458.59344.
MS (GC, 70 eV): m/z (%) = 442 (100) [M+], 427 (90).
HRMS (ESI): m/z [M + H]+ calcd for C28H30N2O3: 443.22564;
found: 443.23317.
1-(3,5-Dimethylphenyl)-7-(hexylamino)-2-(4-tolyl)quinolin-
4(1H)-one (9b)
Yellow oil; yield: 0.346 g (79%).
1-(3,5-Dimethylphenyl)-5-[(2-phenylethyl)amino]quinolin-2-(4-
tolyl)-4(1H)-one (8j)
IR (ATR): 3307 (w), 2922 (w), 1596 (s), 1556 (s), 1512 (m), 1441
(s), 1396 (m), 1296 (m), 1220 (m), 1148 (m), 1017 (m), 848 (m),
815 (m), 706 (m), 636 (m) cm–1.
Yellow solid; yield: 0.444 g (97%); mp 154 °C.
IR (ATR): 3207 (w), 2831 (w), 1619 (s), 1586 (m), 1519 (m), 1505
(s), 1441 (s), 1382 (m), 1348 (m), 1307 (m), 1251 (s), 1182 (m),
1125 (s), 1024 (w), 839 (s), 746 (s), 697 (s), 658 (m), 586 (m).
1H NMR (300 MHz, CDCl3): δ = 0.84–0.91 [m,
3 H,
CH3(CH2)4CH2], 1.13–1.30 [m, 6 H, CH3(CH2)4CH2], 1.43–1.50
[m, 2 H, CH3(CH2)4CH2], 2.23 (s, 6 H, 2 × Me), 2.24 (s, 3 H, Me),
2.91–3.00 [m, 2 H, CH3(CH2)4CH2], 4.06 (br s, 1 H, NH), 5.80 (d,
4J = 2.0 Hz, 1 H, CHAr), 6.27 (s, 1 H, CHAr), 6.62 (dd, 3J = 8.7 Hz,
4J = 2.0 Hz, 1 H, CHAr), 6.74 (s, 2 H, CHAr), 6.90–7.04 (m, 5 H,
CHAr), 8.25 (d, 3J = 8.2 Hz, 1 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 13.9, 20.9, 21.1 (Me), 22.5, 26.6,
28.9, 31.5, 43.2 (CH2), 96.9, 111.7 (CHAr), 117.4 (CAr), 127.4,
127.5, 128.2, 129.0, 130.0 (CHAr), 133.3, 138.0, 138.9, 139.3,
144.9, 151.2, 153.1 (CAr).
1H NMR (300 MHz, CDCl3): δ = 2.21 (s, 6 H, 2 × Me), 2.24 (s, 3 H,
Me), 3.05 (t, 3J = 7.5 Hz, 2 H, CH2), 3.47 (t, 3J = 7.5 Hz, 2 H, CH2),
3
5.88 (d, J = 8.1 Hz, 1 H, CHAr), 6.20 (s, 1 H, CHAr), 6.33 (d,
3J = 8.1 Hz, 1 H, CHAr), 6.70 (s, 2 H, CHAr), 6.88–7.03 (m, 5 H,
CHAr), 7.12–7.23 (m, 2 H, CHAr), 7.32–7.33 (m, 4 H, CHAr), 10.38
(s, 1 H, NH).
13C NMR (62.9 MHz, CDCl3): δ = 21.0, 21.2 (Me), 35.4, 44.9
(CH2), 101.8, 103.0 (CH), 111.7 (C), 112.8, 126.3, 17.6, 128.3,
128.5, 128.8, 129.0, 130.0, 132.8, 132.9 (CH), 138.1, 139.0, 139.7,
145.5, 151.2, 152.5, 181.5 (C).
MS (GC, 70 eV): m/z (%) = 458 (3) [M+], 367 (100).
HRMS (ESI): m/z [M + H]+ calcd for C32H31N2O: 459.24309;
MS (GC, 70 eV): m/z (%) = 438 (54) [M+], 367 (100).
HRMS (ESI): m/z [M + H]+ calcd for C30H35N2O: 439.27439;
found: 439.27378.
found: 459.24347.
Synthesis 2013, 45, 205–218
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-Quinolones by Domino Amination and Conjugate Addition Reactions
217
1,1′-[Ethane-1,2-diylbis(4,1-phenylene)]bis[6-fluoro-2-(4-tol-
yl)quinolin-4(1H)-one] (10a)
1H NMR (300 MHz, CDCl3): δ = 1.48 (d, 3J = 6.8 Hz, 3 H,
CHCH3), 1.54 (d, J = 6.8 Hz, 3 H, CHCH3), 2.28 (s, 3 H, Me),
4.39–4.54 (m, 2 H, 2 × CHCH3), 5.54 (s, 1 H, CHAr), 5.95–6.08 (m,
2 H, CHAr), 7.06 (s, 4 H, CHAr), 7.09–7.32 (m, 10 H, CHAr), 7.47–
7.52 (m, 1 H, CHAr), 9.22 (s, 1 H, NH), 11.19 (d, 1 H, J = 10.2 Hz,
NH).
3
Yellow oil; yield: 0.335 g (49%).
IR (ATR): 3033 (w), 2920 (w), 1603 (s), 1510 (s), 1469 (s), 1384
(m), 1306 (s), 1253 (w), 1180 (m), 1099 (w), 1021 (w), 927 (s), 854
(m), 817 (s), 725 (s), 632 (m), 596 (m), 553 (s) cm–1.
13C NMR (62.9 MHz, CDCl3): δ = 21.3, 24.6, 25.1 (Me), 53.0, 54.0
(CH), 95.1 (CH), 99.0 (d, J = 25.0 Hz, CH), 101.5 (d, J = 25.0 Hz,
CH), 117.5 (C), 125.7, 125.8, 126.8, 126.9, 127.6, 128.6, 128.7,
128.9 (CH), 130.8 (d, J = 200.0 Hz, CH), 131.7 (d, J = 11.4 Hz,
CH), 133.4, 139.2 (C), 144.7 (d, J = 18.7 Hz, C), 151.4 (d, J = 11.4
Hz, C), 163.5, 165.0, 167.5, 191.4 (C).
19F NMR (282 MHz, CDCl3): δ = –107.0.
MS (GC, 70 eV): m/z (%) = 478 (3) [M+], 373 (84), 355 (18), 240
1H NMR (300 MHz, DMSO-d6): δ = 2.20 (br s, 6 H, 2 × CH3), 2.85
3
(br s, 4 H, 2 × CH2), 6.38 (s, 2 H, CHAr), 6.82 (dd, J = 9.4 Hz,
3J = 4.4 Hz, 2 H, CHAr), 6.90–7.06 (m, 16 H, CHAr), 7.12–7.19 (m,
2 H, CHAr), 8.11 (dd, 3J = 8.8 Hz, 3J = 3.0 Hz, 2 H, CHAr).
13C NMR (62.9 MHz, CDCl3): δ = 21.2 (Me), 37.3 (CH2), 110.8 (d,
J = 22.3 Hz, CH), 112.0 (CH), 120.1 (d, J = 8.8 Hz, CH), 128.4 (d,
J = 8.8 Hz, CH), 127.5 (d, J = 6.7 Hz, C), 128.6, 129.1, 129.6, 129.9
(CH), 132.7, 137.2, 138.6, 139.2, 141.9, 154.2, 157.2, 161.1 (C),
176.9 (d, J = 2.5 Hz, C).
19F NMR (282 MHz, CDCl3): δ = –117.6.
MS (EI, 70 eV): m/z (%) = 684 (100) [M+], 342 (44), 314 (10), 226
(100), 105 (74).
HRMS (ESI): m/z [M + H]+ calcd for C32H32N2O: 479.24932;
found: 479.24955.
(43).
HRMS (EI): m/z [M+] calcd for C46H34F2N2O2: 684.25829; found:
684.258764.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
1,1′-Hexane-1,6-diylbis[6-fluoro-2-(4-tolyl)quinolin-4(1H)-one]
(10b)
White solid; yield: 0.417 g (71%); mp >350 °C.
References
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IR (ATR): 1613 (w), 1479 (s), 1417 (s), 1293 (w), 1154 (w), 1087
(w), 931 (w), 859 (m), 828 (w), 740 (w) cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.80 (br s, 4 H, 2 × CH2), 1.41
(br s, 4 H, 2 × CH2), 2.36 (s, 6 H, Me), 3.96 (br s, 4 H, 2 × CH2),
5.89 (s, 2 H, CHAr), 7.28 (m, 8 H, CHAr), 7.62–7.68 (m, 2 H, CHAr),
7.84–7.90 (m, 4 H, CHAr).
13C NMR: not recorded (low solubility).
MS (GC, 70 eV): m/z (%) = 588 (44) [M+], 266 (33), 207 (21), 150
(19).
HRMS (ESI): m/z [M + H]+ calcd for C38H35F2N2O2: 589.26611;
found: 589.26599.
(2Z)-1-{2-Fluoro-6-[(1-phenylethyl)amino]phenyl}-3-(4-tolyl)-
3-[(1-phenylethyl)amino]prop-2-en-1-one (11a)
Yellow solid; yield: 0.33 g (69%); mp 154–156 °C.
IR (ATR): 3342 (w), 2976 (w), 1613 (m), 1557 (s), 1489 (s), 1449
(s), 1412 (m), 1333 (s), 1267 (m), 1241 (m), 1205 (m), 1140 (m),
1085 (m), 1016 (m), 871 (w), 819 (m), 800 (s), 752 (s), 697 (s), 670
(m), 576 (m) cm–1.
3
1H NMR (300 MHz, CDCl3): δ = 1.52 (d, J = 6.8 Hz, 6 H, 2 ×
CHCH3), 2.30 (s, 3 H, Me), 4.44–4.46 (m, 1 H, CHCH3), 4.54–4.64
(m, 1 H, CHCH3), 5.57 (d, 3J = 4.6 Hz, 1 H, NH), 6.07 (d, 3J = 8.8
Hz, 1 H, CHAr), 6.12–6.19 (m, 1 H, CHAr), 6.81–6.88 (m, 1 H,
CHAr), 7.07–7.42 (m, 14 H, CHAr), 7.86–7.91 (m, 1 H, CHAr), 11.49
(d, 1 H, J = 10.2 Hz, NH).
13C NMR: not recorded (low solubility).
19F NMR (282 MHz, CDCl3): δ = –108.9.
MS (GC, 70 eV): m/z (%) = 478 (2) [M+], 373 (87), 355 (31), 240
(100), 105 (100).
HRMS (ESI): m/z [M + H]+ calcd for C32H32FN2O5: 479.24932;
found: 479.25022.
(2Z)-1-{4-Fluoro-2-[(1-phenylethyl)amino]phenyl}-3-[(1-
phenylethyl)amino]-3-(4-tolyl)prop-2-en-1-one (11b)
Yellow solid; yield: 0.306 g (64%); mp 174–176 °C.
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(s), 1451 (s), 1371 (w), 1338 (m), 1303 (m), 1279 (m), 1191 (s),
1138 (m), 1105 (s), 1017 (m), 908 (w), 827 (m), 775 (s), 697 (s), 592
(m) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 205–218

218
V. O. Iaroshenko et al.
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(13) Crystallographic data (excluding structure factors) for
compounds 5g, 5q, 6b, 8b, and 11a have been deposited
with the accession numbers 868711, 868712, 868715,
868716, and 907162, respectively, and can be obtained free
of charge from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; Fax:
Sosnovskikh, V. Ya.; Ostrovskyi, D.; Dudkin, S.; Kotljarov,
A. V.; Miliutina, M.; Savych, I.; Tolmachev, A. A. Synthesis
2010, 2749. (g) Iaroshenko, V. O.; Ostrovskyi, D.;
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web
site: www.ccdc.cam.ac.uk/conts/retrieving.html.
Synthesis 2013, 45, 205–218
© Georg Thieme Verlag Stuttgart · New York