Regioselective functionalization of quinolin-4(1H)-ones via sequential palladium-catalyzed reactions

Article abstract of DOI:10.1016/j.tet.2011.05.134

A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alkyl-6-bromo-3-iodoquinolin-4(1H)-one is described, based on regioselective sequential palladium-catalyzed cross-coupling reactions, namely Suzuki-Miyaura, Sono

Full text of DOI:10.1016/j.tet.2011.05.134

Tetrahedron 67 (2011) 5776e5783
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective functionalization of quinolin-4(1H)-ones via sequential
palladium-catalyzed reactions
*
Claudia Mugnaini, Chiara Falciani, Maria De Rosa, Antonella Brizzi, Serena Pasquini, Federico Corelli
ꢀ
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alkyl-6-
bromo-3-iodoquinolin-4(1H)-one is described, based on regioselective sequential palladium-catalyzed
cross-coupling reactions, namely SuzukieMiyaura, Sonogashira and aminocarbonylation reactions, un-
der microwave irradiation. Good substrate generality, ease of execution and practicability make this
method exploitable for the generation of libraries of chemically diverse 4-quinolones.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 February 2011
Received in revised form 6 May 2011
Accepted 31 May 2011
Available online 12 June 2011
Keywords:
Cross-coupling
Heterogeneous catalysis
Homogeneous catalysis
Palladium
Quinolin-4(1H)-ones
O
O
O
1. Introduction
R3
R2
Br
I
Br
Quinolin-4(1H)-ones constitute a major class of nitrogen con-
taining heterocycles,1 resulting among the mostcommon frameworks
present in the bioactive molecules.2 While 4-quinolone-3-carboxylic
acids are one of the largest classes of antimicrobial agents used
worldwide, variously substituted quinolin-4(1H)-one derivatives
have shownawiderange ofdifferentpharmacologicalactivities,3 such
as, for instance, antiinflammatory,4 antitumour,5 anxiolytic,6 anti-
ischemic,7 antiviral activity.8,9 Due to their synthetic accessibility and
to the possibility of functionalization at different position of the
molecule, quinolin-4(1H)-ones represent an attractive platform for
the design of combinatorial libraries.10
In the context of our ongoing research in the area of 4-quinolones
as anti-HIV-1 agents11 and cannabinoid ligands,12 we became in-
terested in the development of an efficient synthetic methodology
enabling the rapid access to a number of 3,6-disubstituted 1-
alkylquinolin-4(1H)-ones of general structure 1 (Scheme 1).
Although the halide selectivity (I>Br) for various Pd-mediated
CeC bond forming reactions is well known, to our knowledge it
has not been exploited to carry out site-selective functionalization
of the 4-quinolone scaffold.13
N
N
H
N
H
R1
1
2
3
Scheme 1. Retrosynthetic analysis.
key intermediate for the preparation of compounds characterized
by different substituents at the 1, 3 and 6-positions through N-al-
kylation followed by sequential regioselective MW-assisted palla-
dium-catalyzed reactions.14,15 Such an approach would offer the
distinctive advantage of enhancing chemical diversity in the last
three synthetic steps, affording combinatorial libraries of 4-
quinolone derivatives.
2. Results and discussion
6-Bromoquinolin-4(1H)-one 316 was initially prepared according
to the classic method for the synthesis of 4-quinolones, which relies
on the GouldeJacobs reaction between a suitablysubstituted aniline
and a dialkyl alkoxymethylenemalonate followed by Lappin cycli-
zation, hydrolysis of the ester function and decarboxylation. Despite
the good efficiency of this reaction sequence in terms of yield (67%)
and ease of execution, we found that the whole process was time
consuming and not in line with an expeditious preparation of the
target compounds. Accordingly, a two-step MW-assisted synthesis
It was speculated that 6-bromo-3-iodoquinolin-4(1H)-one 2,
generated from 6-bromoquinolin-4(1H)-one 3, could represent the
* Corresponding author. E-mail address: corelli@unisi.it (F. Corelli).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.134

C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
5777
was set up, reacting commercially available 4-bromoaniline and
ethyl propiolate to give the corresponding 3-anilinoacrylate, which
was then cyclized to give the final compound 3 in 35% overall yield
(Scheme 2).17 Although the yield may appear modest if compared
with the one obtained with the classical approach, this procedure
has the advantage of ensuring a very fast access (40 min total re-
action time for the two steps) to the target compound. Treatment of
3 with N-iodosuccinimide (NIS) for 3 min at room temperature
provided the intermediate 2, which delivered the corresponding
N-alkylated products 4aed by reaction with the appropriate alkyl
halide.
Next, we tested the chemoselectivity of the cross-coupling re-
action between 6-bromo-3-iodoquinolin-4(1H)-one 4a and phe-
nylboronic acid without further optimization of the reaction
conditions, and the results are shown in Table 1 (entry 1).
The expected compound 7a was obtained in 80% isolated yield
without concurrent formation of regioisomeric and/or bis-coupling
products, demonstrating the chemoselective functionalization of 3-
position. With this promising result in hand, we applied the same
reaction protocol to substrates 4aec and various boronic acids
(Table 1, entries 2e6).
All the reactions afforded the desired products 7bef in good
isolated yield, with the exception of those employing 2-
furanboronic acid (entry 3) and 4-methoxyphenylvinylboronic
acid (entry 4), where 7c and 7d were obtained in moderate yield
along with not identified degradation products. The less reactive
alkenylboronic acid required to increase the reaction temperature
to 90 ꢀC, but this SuzukieMiyaura reaction afforded compound 7d
in a yield (47%) that is in line with the yield (42e65%) reported
recently for the preparation of (E)-1-methyl-3-styrylquinolin-
4(1H)-ones by a Heck reaction,19 with the advantage of avoiding the
possible concurrent formation of branched regioisomers. In all
cases, complete conversion of substrates 4aec was observed by 1H
NMR of the crude reaction mixture, accompanied by formation of
the target compounds 7bef. However, when a slightly higher ex-
cess (1.5 equiv) of boronic acid was used, traces of 3,6-disubstituted
product also formed, as expected.
O
O
R1-X, K2CO3, DMF
(65-82% yield)
Br
I
Br
I
N
H
N
R1
2
4a: R = methyl
4b: R = ethyl
4c: R = cyclopropylmethyl
4d: R = n-pentyl
Scheme 2. Synthesis of 1-alkyl-6-bromo-3-iodoquinolones 4aed.
As a first step, we started to set up the mildest reaction condi-
tions able to ensure the complete conversion of the starting ma-
terial by replacement of iodine at 3-position using Pd(OAC)2 as the
catalyst. To our delight, we found that the model substrate 3-iodo-
1-methylquinolin-4(1H)-one 518 could be converted to the corre-
sponding 3-phenyl derivative 6 (Scheme 3) in 75% isolated yield
and with 100% conversion of the starting material 5 via Suzu-
kieMiyaura reaction with phenylboronic acid under standard
conditions [Pd(OAc)2 (10 mol %), PPh3 (30 mol %), 2.0 M Na2CO3
(2.5 equiv), DME/EtOH (1.5:1), MW, 5 min, 70 ꢀC].
Further elaboration of compounds 7aee into trisubstituted
quinolones 1aeg was accomplished through sequential Suzu-
kieMiyaura cross-coupling reactions by exploiting the reactivity of
bromine at 6-position. After some preliminary tests, we found that
this reaction could be performed under the same conditions used to
generate compounds 7, by increasing the reaction temperature to
80 ꢀC (Table 2).
The reactions proceeded smoothly to furnish the final tri-
substituted quinolones in moderate (1a) or good yield (1beg), with
complete conversion of the substrate 7 to product.
These results demonstrated that sequential SuzukieMiyaura
arylation at 3- and 6-position of 1-substituted 6-bromo-3-
iodoquinolin-4(1H)-ones can be carried out regioselectively pro-
vided the reaction temperature be carefully controlled. From the
viewpoint of efficiency, one-pot sequential reactions of easily
available (hetero)aryl dihalides with a single catalyst are desirable,
and so far not many successful examples have been reported.20
Therefore, we considered the possibility to introduce chemical di-
versity at 3- and 6-position of compound 4b by one-pot sequential
SuzukieMiyaura reactions. Accordingly, taking advantage of the
possibility to attain complete conversion of 4a after the first
PhB(OH)2 (1.2 eq.)
Pd(OAc)2 (10 mol %)
PPh3 (30 mol %)
O
O
Ph
I
Na2CO3 (2.0 M in H2O) (2.5 eq.)
DME/EtOH (1.5:1)
N
CH3
N
CH3
MW, 70 °C, 5 min
6
5
100% conversion
75% isolated yield
Scheme 3. SuzukieMiyaura reaction on the model substrate 5.
Table 1
Cross-coupling reactions between 1-substituted 6-bromo-3-iodoquinolin-4(1H)-ones 4aec and boronic acids
O
O
R2 B(OH)2
Br
Pd(OAc)2, PPh3
R2
Br
I
N
N
2.0 M Na2CO3
DME/EtOH
R1
R1
MW, 70 °C, 5 min
4a-c
7a-f
Entry
Substrate
R2-B(OH)2
4-Quinolone-R1,R2
Yielda (%)
1
2
3
4
5
6
4a
4a
4a
4a
4b
4c
R2¼phenyl
R2¼4-tolyl
R2¼2-furyl
7a: R1¼Me, R2¼phenyl
80
83
7b: R1¼Me, R2¼4-tolyl
7c: R1¼Me, R2¼2-furyl
49
R2¼(E)-2-(4-methoxyphenyl)vinyl
R2¼4-tolyl
7d: R1¼Me, R2¼(E)-2-(4-methoxyphenyl)vinyl
7e: R1¼Et, R2¼4-tolyl
47b
83
R2¼4-chlorophenyl
7f: R1¼cyclopropylmethyl, R2¼4-chlorophenyl
84
a
Isolated yield based on substrate 4.
b
Reaction performed at 90 ꢀC.

5778
C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
Table 2
Synthesis of 1-alkyl-3,6-diarylquinolin-4(1H)-ones 1aeg
O
O
R3 B(OH)2
R3
R2
Br
R2
Pd(OAc)2, PPh3
N
N
2.0 M Na2CO3
DME/EtOH
R1
R1
MW, 80 °C, 5 min
1a-g
7a-e
Entry
Substrate
R3-B(OH)2
4-Quinolone-R1,R2,R3
Yielda (%)
1
2
3
4
5
6
7
7a
7a
7a
7b
7c
7d
7e
R3¼4-(trifluoromethoxy)phenyl
1a: R1¼Me, R2¼phenyl, R3¼4-(trifluoromethoxy)phenyl
50
99
88
87
98
67
76
R3¼3-pyridinyl
1b: R1¼Me, R2¼phenyl, R3¼3-pyridinyl
R3¼3-chlorophenyl
R3¼4-cyanophenyl
R3¼3-chlorophenyl
R3¼3-chlorophenyl
R3¼3-chlorophenyl
1c: R1¼Me, R2¼phenyl, R3¼3-chlorophenyl
1d: R1¼Me, R2¼4-tolyl, R3¼4-cyanophenyl
1e: R1¼Me, R2¼2-furyl, R3¼3-chlorophenyl
1f: R1¼Me, R2¼(E)-2-(4-methoxyphenyl)vinyl, R3¼3-chlorophenyl
1g: R1¼Et, R2¼4-tolyl, R3¼3-chlorophenyl
a
Isolated yield based on substrate 7.
arylation reaction, the preparation of compounds 1c and 1d from
4a without isolation and purification of the intermediates 7a and
7b was investigated (Table 3).
toluene with 1,4-dioxane as a solvent and used MW irradiation
(120 ꢀC, 5 min) instead of conventional heating (reflux, 2 h). Under
these conditions, product 7f was obtained in 58% yield. This reaction
Table 3
One-pot double Suzuki reactions of 4a with different arylboronic acids
O
O
R2 B(OH)2
Pd(OAc)2, PPh3
R3
R2
Br
I
R3 B(OH)2, PPh3
2.0 M Na2CO3
DME/EtOH
2.0 M Na2CO3
N
CH3
N
CH3
MW, 80 °C, 5 min
MW, 70 °C, 5 min
4a
1c,d
Entry
R2-B(OH)2
R3-B(OH)2
4-Quinolone-R2, R3
Yielda (%)
1
2
R2¼phenyl
R3¼3-chlorophenyl
1c: R2¼phenyl, R3¼3-chlorophenyl
69
55
R3¼4-tolyl
R3¼4-cyanophenyl
1d: R3¼4-tolyl, R3¼4-cyanophenyl
a
Overall isolated yield based on substrate 4a.
Thus, 4a and phenylboronic acid (entry 1) were reacted under
the conditions described in Table and thereafter 3-
worked in a satisfactory manner even on substrate 2 (entry 6), de-
livering product 8 in 65% yield, with no further conversion to furo
[3,2-c]quinoline derivatives.21
1
chlorophenylboronic acid (1.2 equiv) was added to the crude re-
action mixture, along with more triphenylphosphine (30 mol %) (to
avoid catalyst decomposition) and base (2 M Na2CO3, 2.5 equiv),
and the mixture was subjected to MW irradiation at 80 ꢀC for 5 min
to give compound 1c in 69% overall yield. Similarly, compound 1d
(entry 2) was obtained in 55% overall yield through the one-pot
sequential reaction of 4a with 4-methylphenylboronic acid first
and then with 4-cyanophenylboronic acid. The one-pot procedure
allowed the preparation of the desired trisubstituted derivatives in
overall yields comparable to or slightly lower than those obtained
in the stepwise synthesis (70% for 1c and 72% for 1d), but with
a total reaction time of only 10 min without isolation of the mon-
oarylated intermediate.
Once we had demonstrated that different aryl groups can be
regioselectively introduced at 3- and 6-position of the 4-quinolone
scaffold by SuzukieMiyaura reactions, we considered other
palladium-catalyzed reactions to be used to decorate the bicyclic
core in order to enhance the chemical diversity. The results of these
experiments are reported inTable 4. Although Sonogashira reactions
on both 3-iodoquinolin-4(1H)-ones and 4-bromoquinolin-2(1H)-
ones have been already reported,21,22 in the reaction between 4a and
trimetylsilylacetylene (TMSA) (entry 1) the best conversions and
isolated product yields were achieved by employing the procedure
developed by Babudri et al.,23 based on the use of a large excess
(250 equiv) of diisopropylamine as base, though we replaced
Pd-catalyzed carbonylation of aryl halides in the presence of
primary or secondary amines provides different benzoic acid am-
ides in a smooth manner. The combination of microwave heating
and in situ release of CO from Mo(CO)6 has been proven to enable
the fast development of new easy-to-execute carbonylation pro-
tocols.24e26 Based on our previous applications of amino-
carbonylation reactions on quinolone derivatives,11 we initially
adopted the experimental protocol reported by Larhed et al.27 Thus,
substrate 4a (entry 2) was reacted with aniline according to
method B to provide compound 7h in 38% yield. Similarly, the
conversion of 4d (entry 5) into 7k was accomplished in a moderate
yield of 25%. Slight modifications of the experimental conditions,
such as in entry 3, did not improve the reaction yield and com-
pound 7i was isolated in 36% yield. Even when the procedure re-
cently described by Salvadori et al.,28 based on the use of gaseous
CO and Pd/C as the catalyst (method C), was applied to substrate 4c
(entry 4), the aminocarbonylation product 7j was obtained in
a similar yield of 35%.
Cross-coupling reactions at 6-position of substrates 7a,fei,k to
produce the trisubstituted 4-quinolones 1heo were carried out
using the same procedures adopted to displace iodine at 3-position,
although some modifications were usually required due to the
lower reactivity of bromine compared to iodine (Table 5). In all
cases MW irradiation time and/or temperature had to be

C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
5779
Table 4
disclosed herein represent a general and practical synthesis of
1,3,6-trisubstituted quinolin-4(1H)-ones of potential pharma-
ceutical interest. Good substrate generality, ease of execution and
practicability make this method exploitable for the generation of
libraries of 4-quinolones characterized by remarkable chemical
diversity.
Sonogashira and aminocarbonylation reactions of substrates 2, and 4a,b,d
O
O
Br
R2
Br
I
Methods A-C
N
N
R1
R1
4. Experimental section
4.1. General
2, 4a,b,d
7g-k, 8
Entry Substrate
Product
Method Yielda (%)
Merck silica gel 60 was used for flash chromatography
(23e400 mesh). IR spectra were recorded on a PerkineElmer BX FT-
IR system using CHCl3 as the solvent or a Nujol dispersion. 1H NMR
and 13C NMR were recorded at 200 MHz and 50 MHz, respectively,
on a Brucker AC200F spectrometer and at 400 MHz and 100 MHz
on a Brucker Advance DPX400. Chemical shifts are reported relative
to tetramethylsilane at 0.00 ppm. Mass spectral data were de-
termined by direct insertion at 70 eV with a VG70 spectrometer.
Melting points were determined on a Gallenkamp apparatus and
are uncorrected. Microwave irradiations were conducted using
a CEM Discover Synthesis Unit. Elemental analyses were performed
on a PerkineElmer PE 2004 Elemental Analyzer and the data for C,
H and N are within 0.4% of the theoretical values.
1
2
4a: R1¼Me
4a: R1¼Me
A
B
58
38
7g: R1 = Me, R2
7h: R1 = Me, R2
=
Si
O
Ph
=
N
H
3
4
5
4a: R1¼Me
Bb
C
36
35
25
O
4b: R1¼Et
7j: R1 = Et, R2
=
N
O
4d: R1¼n-pentyl
B
4.2. General procedure for the synthesis of 3-substituted
quinolin-4(1H)-ones 7aef
8: R1 = H, R2
=
A microwave vial was charged with 4aec (0.20 mmol), the
appropriate arylboronic acid (0.24 mmol), Pd(OAc)2 (4.4 mg,
0.02 mmol), PPh3 (16 mg, 0.06 mmol), 2 M Na2CO3 (0.25 mL),
DME (0.75 mL), EtOH (0.5 mL) and exposed to microwave irra-
diation at 70 ꢀC for 5 min. After cooling, the reaction mixture was
diluted with dichloromethane and filtered through Celite. The
organic layer was washed with brine, dried and concentrated to
a residue, which was purified by flash chromatography [silica gel,
95/5 (v/v) dichloromethane/methanol] to provide the title com-
pounds 7aef.
6
2: R1¼H
A
65
Si
Reagents and conditions: method A: TMSA, CuI, Pd(PPh3)2Cl2, i-Pr2NH, dioxane,
MW, 120 ꢀC, 5 min; method B: appropriate amine, Pd(OAc)2, Mo(CO)6, DBU, THF,
MW, 110 ꢀC, 10 min; method C: morpholine, Pd/C, CO (130 psi), DBU, DMF, MW,
100 ꢀC, 10 min.
a
Isolated yield based on substrates 2 and 4a,b,d.
Irradiation time: 5 min.
b
optimized, while for the conversion of 7a into 1h by Sonogashira
coupling (entry 1), the reaction was best performed under con-
ventional heating (reflux, 24 h). Generally, harder conditions were
necessary to functionalize the 6-position while, on the other hand,
the increased structural complexity made substrates 7 more prone
to decomposition and side-products formation. As a result, cross-
coupling reactions at 6-position proceeded with slightly lower ef-
ficiency, leading to products 1heo in 27e81% yield. It is worth
noting that attempts to perform the aminocarbonylation reaction
on substrate 7f with 4-methoxybenzylamine according to method
D only afforded the debrominated quinolone along with de-
composition products, while compound 1i (entry 2) could be
obtained using the procedure described under method B in 30%
yield together with 53% of starting material 7f, which was easily
separated by chromatography and reused in another run.
Finally, we wish to underline that the two-step transformation of
4d into 1o by sequential aminocarbonylation and SuzukieMiyaura
reactions represents a new synthesis of N-(adamantan-1-yl)-6-
(furan-2-yl)-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide
(1o), possibly the highest affinity and most selective cannabinoid
type 2 receptor ligand developed to date, which compares favour-
ably in terms of ease of execution and overall yield (6%) with the
previous synthesis (8%).12
4.2.1. 6-Bromo-1-methyl-3-phenylquinolin-4(1H)-one (7a). Rf 0.70
(CH2Cl2/MeOH 95/5); mp 185e186 ꢀC (MeOH); 1H NMR (400 MHz,
CDCl3):
d
8.64 (d, J¼2.1 Hz, 1H), 7.70 (dd, Jortho¼8.9 Hz, Jmeta¼2.1 Hz,
1H), 7.64e7.63 (m, 2H), 7.61 (s, 1H), 7.42e7.38 (m, 2H), 7.33e7.29
(m, 1H), 7.26 (d, Jortho¼8.9 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 174.1, 142.7, 138.7, 135.0, 134.9, 130.0, 128.5, 128.3, 127.3,
122.2, 117.5, 117.2, 40.8; IR (CHCl3):
315. Anal. Calcd for C16H12BrNO: C, 61.17; H, 3.85; N, 4.46; found: C,
61.35; H, 3.91; N, 4.36.
n
1626 cmꢁ1; MS: m/z (Mþþ1)
4.2.2. 6-Bromo-1-methyl-3-(4-methylphenyl)quinolin-4(1H)-one
(7b). Rf 0.87 (CH2Cl2/MeOH 95/5); mp 226e227 ꢀC (MeOH); 1H
NMR (200 MHz, CDCl3):
d
8.59 (d, J¼2.8 Hz, 1H), 7.64 (dd, Jor-
¼8.8 Hz, Jmeta¼1.8 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J¼7.9 Hz, 1H),
tho
7.24e7.15 (m, 4H), 3.76 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3): 174.9, 142.6, 138.9, 137.3, 135.1, 132.2, 130.4, 129.3, 128.6,
d
122.8, 117.7, 117.2, 112.5, 41.0, 21.5; IR (CHCl3): n
1625 cmꢁ1; MS: m/z
(Mþþ1) 329. Anal. Calcd for C17H14BrNO: C, 62.21; H, 4.30; N, 4.27;
found: C, 62.50; H, 4.39; N, 4.12.
4.2.3. 6-Bromo-1-methyl-3-(furan-2-yl)quinolin-4(1H)-one (7c). Rf
0.75 (CH2Cl2/MeOH 95/5); mp 209e210 ꢀC (MeOH); 1H NMR
(200 MHz, CDCl3):
d
8.59 (d, J¼2.0 Hz, 1H), 8.05 (s, 1H), 7.66 (dd,
3. Conclusion
Jortho¼9.5 Hz, Jmeta¼2.6 Hz, 1H), 7.35 (d, J¼3.5 Hz, 1H), 7.25e7.21 (m,
2H), 6.51e6.48 (m, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3):
In summary, the sequential palladium-catalyzed cross-cou-
pling reactions of 1-alkyl-6-bromo-3-iodoquinolin-4(1H)-one
d 172.0, 148.2, 140.2, 139.5, 137.8, 134.6, 123.5, 127.6, 117.7, 117.3,
111.8, 109.2, 41.2; IR (CHCl3):
n
1632 cmꢁ1; MS: m/z (Mþþ1) 305.

5780
C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
Table 5
Synthesis of trisubstituted quinolones 1heo by various Pd-catalyzed reactions
O
O
R3
R2
Br
R2
Methods A-D
N
N
R1
R1
7a, 7f-i, 7k
1h-o
Entry
Substrate
Product
Method
Yielda (%)
O
1
7a: R1¼Me, R2¼Ph
Ab
56
N
Me
1h
Cl
O
O
N
H
2
3
B
C
30c
7f: R1
=
, R2 = 4-Cl-Ph
MeO
N
1i
NC
O
Si
7g: R1 = Me, R2
=
44
Si
N
Me
1j
O
Si
7g: R1 = Me, R2
=
4
A
27
Si
N
Me
1k
O
N
O
Cl
N
H
O
5
6
7h: R1 = Me, R2
=
Cd
55
30
N
H
Me
1l
O
O
O
N
H
N
H
O
O
7i: R1 = Me, R2
=
D
N
Me
N
H
1m
Si
O
O
N
7
8
Ae
52
81
7i: R1 = Me, R2
=
H
N
N
H
Me
1n
O
O
O
N
O
Cf
7k: R1 = n-pentyl, R2
=
H
N
N
H
1o
Reagents and conditions: method A: appropriate alkyne, CuI, Pd(PPh3)2Cl2, i-Pr2NH, dioxane, MW, 150 ꢀC, 30 min; method B: 4-methoxybenzylamine, Pd(PPh3)2Cl2, CO
(120 psi), DIPEA, THF, MW, 130 ꢀC, 2ꢂ20 min; method C: boronic acid, Pd(OAc)2, PPh3, Na2CO3, DME/EtOH, MW, 80 ꢀC, 5 min; method D: appropriate amine, Pd(OAc)2,
Mo(CO)6, DBU, THF, MW, 150 ꢀC, 5 min.
a
Isolated yield based on substrates 7a, 7fei, 7k.
Reaction performed under conventional heating (reflux, 24 h).
Compound 7f (53%) was recovered.
b
c
d
Irradiation time: 10 min.
e
Reaction performed at 120 ꢀC for 5 min.
f
Reaction performed at 150 ꢀC for 10 min; see Ref. 12.

C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
5781
Anal. Calcd for C14H10BrNO2: C, 55.29; H, 3.31; N, 4.61; found: C,
55.00; H, 3.20; N, 4.77.
C21H16N2O: C, 80.75; H, 5.16; N, 8.97; found: C, 80.55; H, 5.25; N,
9.15.
4.2.4. 6-Bromo-3-[2-(4-methoxyphenyl)ethen-1-yl]-1-
4.3.3. 6-(3-Chlorophenyl)-1-methyl-3-phenylquinolin-4(1H)-one
methylquinolin-4(1H)-one (7d). Rf 0.83 (CH2Cl2/MeOH 99/1); mp
(1c). Rf 0.61 (CH2Cl2/MeOH 95/5); mp 210e211 ꢀC (MeOH); 1H
152e154 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.63 (d, J¼4.0 Hz, 1H),
NMR (400 MHz, CDCl3):
d
8.76 (d, J¼2.0 Hz, 1H), 7.84 (dd, Jor-
7.71e7.70 (m, 1H), 7.69 (s, 1H), 7.53 (d, J¼16.0 Hz, 1H), 7.45 (d,
J¼8.0 Hz, 2H), 7.26 (m, 1H), 6.99 (d, J¼16.0 Hz, 1H), 6.88 (d,
J¼8.0 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz,
¼9.0 Hz, Jmeta¼2.1 Hz, 1H), 7.70e7.65 (m, 4H), 7.56 (dd, Jor-
¼7.6 Hz, Jmeta¼6.4 Hz, 1H), 7.44 (d, J¼8.7 Hz, 1H), 7.41e7.28 (m,
tho
tho
5H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 176.0, 142.8, 141.7,
CDCl3):
d
174.9, 159.3, 143.2, 141.8, 138.2, 134.8, 130.1, 129.5, 128.0,
139.8, 135.2, 135.1, 130.9, 130.4, 128.9, 128.6, 127.8, 127.6, 127.4,
119.6, 117.9, 117.5, 117.4, 114.3, 114.1, 55.5, 41.2, 40.9, 29.9; IR
125.8, 125.5, 122.5, 116.2, 41.1; IR (CHCl3): n
1630 cmꢁ1; MS: m/z
(CHCl3):
n
1618 cmꢁ1; MS: m/z (Mþþ1) 371. Anal. Calcd for
(Mþþ1) 346. Anal. Calcd for C22H16ClNO: C, 76.41; H, 4.66; N, 4.05;
C19H16BrNO2: C, 61.64; H, 4.36; N, 3.78; found: C, 61.98; H, 4.50; N,
3.51.
found: C, 76.18; H, 4.54; N, 4.21.
4.3.4. 6-(4-Cyanophenyl)-1-methyl-3-(4-methylphenyl)quinolin-
4.2.5. 6-Bromo-1-ethyl-3-(4-methylphenyl)quinolin-4(1H)-one
4(1H)-one (1d). Rf 0.70 (CH2Cl2/MeOH 95/5); mp 257e258 ꢀC
(7e). Rf 0.75 (CH2Cl2/MeOH 95/5); mp 146e147 ꢀC (MeOH); 1H
(MeOH); 1H NMR (400 MHz, CDCl3):
d
8.80 (d, J¼1.9 Hz, 1H), 7.92
NMR (400 MHz, CDCl3):
d
8.64 (d, J¼2.4 Hz, 1H), 7.66 (dd, Jor-
(dd, Jortho¼8.8 Hz, Jmeta¼1.8 Hz, 1H), 7.81 (d, J¼8.4, 2H), 7.74 (d,
J¼8.4 Hz, 2H), 7.74 (s, 1H), 7.58 (d, J¼7.8 Hz, 2H), 7.53 (d, J¼8.8 Hz,
1H), 7.24 (d, J¼7.8 Hz, 2H), 3.90 (s, 3H), 2.39 (s, 3H); 13C NMR
¼13.2 Hz, Jmeta¼2.5 Hz, 1H), 7.54 (d, J¼7.9 Hz, 2H), 7.28 (d,
tho
J¼9.0 Hz, 1H), 7.21 (d, J¼7.8 Hz, 2H), 4.16 (q, J¼7.3 Hz, 2H) 2.37 (s,
3H), 1.48 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
174.5, 141.2,
(100 MHz, CDCl3): d 176.1, 144.4, 142.6, 140.2, 137.3, 134.4, 133.0,
137.6, 137.0, 134.7, 132.2, 130.3, 129.1, 128.8, 128.4, 122.6, 117.1, 117.0,
132.3, 130.7, 129.3, 128.7, 127.9, 127.6, 126.4, 122.9, 119.1, 116.4, 11.3,
48.2, 21.2, 14.5; IR (CHCl3):
n
1634 cmꢁ1; MS: m/z (Mþþ1) 343. Anal.
41.1, 21.5; IR (CHCl3):
Calcd for C24H18N2O: C, 82.26; H, 5.18; N, 7.99; found: C, 82.47; H,
5.02; N, 8.22.
n
2230, 1625 cmꢁ1; MS: m/z (Mþþ1) 351. Anal.
Calcd for C18H16BrNO: C, 63.17; H, 4.71; N, 4.09; found: C, 63.40; H,
4.55; N, 4.21.
4.2.6. 6-Bromo-3-(4-chlorophenyl)-1-cyclopropylmethylquinolin-
4.3.5. 6-(3-Chlorophenyl)-3-(furan-2-yl)-1-methylquinolin-4(1H)-
4(1H)-one (7f). Rf 0.73 (AcOEt/hexanes 1/1); mp 178e179 ꢀC; 1H
one (1e). Rf 0.85 (CH2Cl2/MeOH 98/2); mp 253e254 ꢀC (AcOEt);
NMR (400 MHz, CDCl3):
d
8.64 (s, 1H), 7.75 (s, 1H), 7.70 (d, J¼8.0 Hz,
1H NMR (400 MHz, CDCl3):
d
8.64 (s, 1H), 7.98 (s, 1H), 7.75 (d,
J¼8.5 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J¼7.2 Hz, 1H), 7.41e7.31 (m,
5H), 6.53 (s, 1H), 3.81(s, 3H); 13C NMR (100 MHz, CDCl3):
173.0,
1H), 7.58 (d, J¼8.0 Hz, 2H), 7.40 (d, J¼8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz,
2H) 4.00 (d, J¼4.0, 2H), 1.32 (m, 1H), 0.73 (m, 2H), 0.43 (m, 2H); 13C
d
NMR (100 MHz, CDCl3):
d
174.2, 141.4, 138.2, 134.9, 133.7, 132.9,
148.5, 141.2, 140.0, 139.4, 138.6, 134.8, 134.7, 130.2, 130.1, 127.6,
127.0, 126.5, 125.1, 124.7, 116.3, 113.0, 111.9, 109.0, 41.1; IR
130.1, 129.8, 129.1, 128.6, 128.4, 120.9, 117.5, 117.3, 57.4, 10.2, 4.5; IR
(CHCl3):
n
1622 cmꢁ1; MS: m/z (Mþþ1) 389. Anal. Calcd for
(CHCl3):
n
1625 cmꢁ1; MS: m/z (Mþþ1) 336. Anal. Calcd for
C19H15BrClNO: C, 58.71; H, 3.89; N, 3.60; found: C, 58.42; H, 3.78; N,
3.79.
C20H14ClNO2: C, 71.54; H, 4.20; N, 4.17; found: C, 71.86; H, 4.32;
N, 4.01.
4.3.6. 6-(3-Chlorophenyl)-3-[2-(4-methoxyphenyl)ethen-1-yl]-1-
4.3. General procedure for the synthesis of 3,6-disubstituted
quinolin-4(1H)-ones 1aeg, 1j, 1l and 1o by SuzukieMiyaura
cross-coupling reaction
methylquinolin-4(1H)-one (1f). Rf 0.53 (CH2Cl2/MeOH 99/1); mp
192e193 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.74 (m, 1H), 7.84 (dd,
Jortho¼8.0 Hz, Jmeta¼4.0 Hz, 1H), 7.71e7.69 (m, 2H), 7.60e7.56 (m,
2H), 7.48e7.30 (m, 5H), 7.04 (d, J¼16.0 Hz, 1H), 6.89 (d, J 8.0 Hz,
¼
The title compounds were prepared from 7aee, 7g, 7h and 7k
according to the same procedure described for the synthesis of
compounds 7aef, by microwave irradiation at 80 ꢀC for 5 min,
unless otherwise reported below.
2H), 3.90 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3):
159.1, 141.5, 138.8, 134.9, 131.0, 130.2, 130.1, 128.0, 127.5, 127.1,
d 176.0,
126.7, 125.2, 120.3, 119.1, 116.1, 114.1, 55.3, 40.9; IR (CHCl3):
n
1630, 1608 cmꢁ1
;
MS: m/z (Mþþ1) 403. Anal. Calcd for
C25H20ClNO2: C, 74.71; H, 5.02; N, 3.49; found: C, 75.01; H, 5.11;
N, 3.29.
4.3.1. 1-Methyl-3-phenyl-6-[(4-trifluoromethoxy)phenyl]quinolin-
4(1H)-one (1a). Rf 0.70 (CH2Cl2/MeOH 95/5); mp 200e201 ꢀC
(MeOH); 1H NMR (200 MHz, CDCl3):
d
8.75 (d, J¼2.4 Hz, 1H), 7.87
4.3.7. 6-(3-Chlorophenyl)-1-ethyl-3-(4-methylphenyl)quinolin-
(dd, Jortho¼8.8 Hz, Jmeta¼2.0 Hz, 1H) 7.72 (s, 2H), 7.67 (s, 1H), 7.63 (s,
4(1H)-one (1g). Rf 0.80 (CH2Cl2/MeOH 95/5); mp 137e138 ꢀC
2H), 7.47 (d, J¼8.9 Hz, 1H), 7.43e7.29 (m, 5H), 3.86 (s, 3H); 13C NMR
(CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
8.80 (d, J¼1.7 Hz, 1H), 7.87
(100 MHz, CDCl3):
d
176.0, 149.1, 142.8, 139.7, 138.7, 135.5, 135.4,
(dd, Jortho¼8.9 Hz, Jmeta¼2.1 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.60 (d,
J¼7.8 Hz, 41 2H), 7.52 (d, J¼8.8 Hz, 1H), 7.42e7.33 (m, 3H), 7.24 (d,
J¼7.8 Hz, 2H) 4.26 (q, J¼7.2 Hz, 2H), 2.39 (s, 3H), 1.55 (t, J¼7.0 Hz,
130.9,128.9,128.7,128.6,127.7,127.4,125.8,122.6,121.6,116.2,112.5,
41.1; IR (CHCl3):
n
1630 cmꢁ1; MS: m/z (Mþþ1) 396. Anal. Calcd for
C23H16F3NO2: C, 69.87; H, 4.08; N, 3.54; found: C, 70.11; H, 4.00; N,
3.35.
3H); 13C NMR (100 MHz, CDCl3):
d 176.0, 138.5, 136.9, 134.9, 134.7,
132.5, 130.5, 130.2, 129.7, 129.0, 128.5, 127.8, 127.5, 127.2, 125.9,
125.2, 122.5, 115.7, 48.2, 21.2, 14.6; IR (CHCl3): n
1635 cmꢁ1; MS: m/z
4.3.2. 1-Methyl-3-phenyl-6-(pyridin-3-yl)quinolin-4(1H)-one
(Mþþ1) 374. Anal. Calcd for C24H20ClNO: C, 77.10; H, 5.39; N, 3.75;
(1b). Rf 0.38 (CH2Cl2/MeOH 95/5); mp 168e169 ꢀC (MeOH); 1H
found: C, 77.40; H, 5.51; N, 3.48.
NMR (200 MHz, CDCl3):
d
8.77 (d, J¼1.8 Hz, 1H), 8.60 (s, 1H), 7.99 (d,
J¼7.9 Hz, 1H), 7.90 (dd, Jortho¼8.6 Hz, Jmeta¼2.2 Hz, 1H), 7.60 (s, 1H),
4.3.8. 6-(4-Cyanophenyl)-1-methyl-3-(trimethylsilylethynyl)quino-
7.65 (d, J¼7.2 Hz, 1H), 7.51 (d, J¼8.8, 1H), 7.43e7.30 (m, 5H), 3.87 (s,
lin-4(1H)-one (1j). Rf 0.36 (CH2Cl2/MeOH, 97/3); mp 230e231 ꢀC
3H); 13C NMR (100 MHz, CDCl3):
d
175.1, 148.9, 148.4, 139.9, 135.4,
(MeOH); 1H NMR (200 MHz, CDCl3):
d
8.62 (s, 1H), 7.86 (dd, Jor-
134.6, 133.4, 130.8, 128.9, 128.6, 127.9, 127.5, 126.0, 122.6, 116.5, 41.1;
¼9.0 Hz, Jmeta¼2.0 Hz, 4H), 7.72 (s, 1H), 7.47 (d, J¼9.0 Hz, 1H), 7.24
tho
IR (CHCl3):
n
1631 cmꢁ1; MS: m/z (Mþþ1) 313. Anal. Calcd for
(s, 1H), 3.83 (s, 3H), 0.25 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 176.0,

5782
C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
147.4, 143.6, 139.4, 134.8, 132.6, 130.7, 127.5, 126.4, 125.4, 118.6,
NMR (400 MHz, CDCl3):
d
8.47 (d, J¼1.9 Hz, 1H), 7.73 (s, 1H), 7.68
116.5, 111.2, 106.7, 98.6, 98.3, 41.0, 29.6; IR (CHCl3):
n
2240,
(dd, Jortho¼8.7 Hz, Jmeta¼6.4 Hz, 1H), 7.54e7.50 (m, 2H), 7.35e7.30
1630 cmꢁ1; MS: m/z (Mþþ1) 357. Anal. Calcd for C22H20N2OSi: C,
(m, 3H), 7.25 (d, J¼3, 1H), 3.75 (s, 3H), 0.25 (s, 9H); 13C NMR
74.12; H, 5.65; N, 7.86; found: C, 74.47; H, 5.55; N, 8.10.
(100 MHz, CDCl3): d 175.4, 147.3, 138.7, 134.8, 131.5, 130.2, 128.4,
128.3, 125.8, 122.7, 119.4, 115.7, 106.5, 98.7, 98.0, 90.4, 88.2, 40.9,
4.3.9. 6-(3-Chlorophenyl)-1-methyl-N-phenylquinolin-4(1H)-one-3-
29.6; IR (CHCl3):
Calcd for C23H21NOSi: C, 77.71; H, 5.95; N, 3.94; found: C, 78.08; H,
6.10; N, 3.66.
n
2149, 1637 cmꢁ1; MS: m/z (Mþþ1) 356. Anal.
carboxamide (1l). Irradiation time: 2ꢂ5 min. Rf 0.51 (CH2Cl2/MeOH
98/2); mp 243e244 ꢀC (MeOH); 1H NMR (200 MHz, CDCl3):
d 12.20
(s, 1H), 8.85 (s, 1H), 8.71 (d, J¼2.0 Hz, 1H), 7.97 (dd, Jortho¼8.8 Hz,
Jmeta¼2.0 Hz, 1H), 7.79e7.68 (m, 3H), 7.60e7.50 (m, 2H), 7.45e7.31
(m, 4H), 7.14e7.07 (m, 1H), 3.99 (s, 1H); 13C NMR (100 MHz,
4.4.5. N-(Adamantan-1-yl)-1-methyl-6-(trimethylsilylethynyl)qui-
nolin-4(1H)-one-3-carboxamide (1n). Rf 0.71 (CH2Cl2/MeOH 98/2);
(CD3)2SO):
d
176.9, 163.0, 148.8, 142.8, 141.0, 139.6, 138.9, 137.2,
mp 298e299 ꢀC; 1H NMR (200 MHz, CDCl3):
d 9.81 (s, 1H), 8.68 (s,
135.3,130.5,129.5,128.9, 128.1,127.7,125.6,124.1,120.6,116.2,112.5,
1H), 8.59 (m, 1H), 7.77e7.73 (m, 1H), 7.39 (d, J¼8.8 Hz, 1H), 3.89 (s,
41.9; IR (CHCl3):
n
1664, 1605 cmꢁ1; MS: m/z (Mþþ1) 389. Anal.
3H), 2.15e2.09 (m, 9H), 1.77e1.71 (m, 6H), 0.24 (s, 9H); 13C NMR
Calcd for C23H17ClN2O2: C, 71.04; H, 4.41; N, 7.20; found: C, 71.34; H,
4.53; N, 6.87.
(100 MHz, CDCl3): d 174.9, 165.3, 148.8, 143.6, 139.4, 135.4, 131.3,
121.2, 115.8, 109.2, 63.7, 51.7, 41.8, 36.6, 29.7, 29.6, 29.4, 12.9; IR
(CHCl3):
n
1660 cmꢁ1; MS: m/z (Mþþ1) 432. Anal. Calcd for
4.3.10. N-(Adamantan-1-yl)-6-(furan-2-yl)-1-pentylquinolin-4(1H)-
one-3-carboxamide (1o). Prepared as described in Ref. 12.
C26H32N2O2Si: C, 72.18; H, 7.46; N, 6.48; found: C, 72.37; H, 7.55; N,
6.26.
4.4. General procedure for the synthesis of 7g, 8, 1h, 1k, 1n by
Sonogashira coupling
4.5. Synthesis of 7h, 7i, 7k and 1m by aminocarbonylation
Reaction using Mo(CO)6
A mixture of the appropriate substrate 2b, 4b, 7a, 7g, 7i
(0.2 mmol), CuI (8 mg, 0.04 mmol), PdCl2(PPh3)2 (14 mg,
0.02 mmol), diisopropylamine (7 mL, 50 mmol), the proper alkyne
A microwave vial was charged with the appropriate substrate
4b, 4e, 7i (0.5 mmol), Pd(OAc)2 (12.3 mg, 0.05 mmol), Mo(CO)6
(phenylacetylene: 55
m
L, 0.5 mmol; TMSA: 40
mL, 0.26 mmol), and
(67 mg, 0.25 mmol), DBU (224 mL, 1.5 mmol), the appropriate
1,4-dioxane (5 mL) was heated by microwaves irradiation at 120 ꢀC
for 5 min (150 ꢀC, 3ꢂ10 min for 1l) or refluxed for 24 h (for 1i). After
cooling, the reaction mixture was diluted with dichloromethane
and filtered through Celite. The organic layer was washed with 1 N
HCl, then with brine, dried and concentrated to a residue, which
was purified by flash chromatography [silica gel, 98/2 (v/v)
dichloromethane/methanol] to give the title compound as a solid.
amine (0.75 mmol), dry THF (5 mL) and subjected to microwave
irradiation at the temperature and for the time reported below.
The reaction mixture was filtered through Celite and evaporated.
The residue was taken up into dichloromethane, washed with
brine and dried. Removal of the solvent left a residue, which was
purified by flash chromatography on silica gel to provide the title
compounds.
4.4.1. 6-Bromo-1-methyl-3-(trimethylsilylethynyl)quinolin-4(1H)-
4.5.1. 6-Bromo-1-methyl-N-phenylquinolin-4(1H)-one-3-
one (7g). Rf 0.84 (CH2Cl2/MeOH, 97/3); mp>300 ꢀC; 1H NMR
carboxamide (7h). Rf 0.33 (AcOEt/EP 2/1); mp 224e225 ꢀC; 1H
(200 MHz, CDCl3):
Jortho¼8.5 Hz, Jmeta¼2.5 Hz, 1H), 7.25 (d, J¼8.5 Hz, 1H), 3.77 (s, 3H),
0.24 (s, 9H); 13C NMR (100 MHz, CDCl3):
174.7, 147.6, 138.0, 135.1,
d
8.55 (d, J¼2.5 Hz, 1H), 7.81 (s, 1H), 7.73 (dd,
NMR (200 MHz, CDCl3): d 12.10 (s, 1H), 8.80 (s, 1H), 8.65 (d,
J¼2.0 Hz, 1H), 7.83 (dd, Jortho¼8.4 Hz, Jmeta¼2.0 Hz, 1H), 7.73 (d,
d
J¼8.4 Hz, 1H), 7.41e7.30 (m, 4H), 7.13e7.05 (m, 1H), 3.98 (s, 3H);
129.1, 127.0, 118.2, 117.6, 106.2, 98.8, 98.2, 41.2, 0.2; IR (CHCl3):
n
13C NMR (100 MHz, (CD3)2SO):
d 177.3, 163.0, 148.8, 144.0, 142.9,
2150, 1635 cmꢁ1
;
MS: m/z (Mþþ1) 335. Anal. Calcd for
138.6, 136.1, 129.9, 128.9, 128.0, 123.9, 120.4, 117.8, 41.7; IR
C15H16BrNOSi: C, 53.89; H, 4.82; N, 4.19; found: C, 53.50; H, 4.70; N,
3.99.
(CHCl3):
n
1665 cmꢁ1; MS: m/z (Mþþ1) 358. Anal. Calcd for
C17H13BrN2O2: C, 57.16; H, 3.67; N, 7.84; found: C, 57.46; H, 3.80;
N, 7.50.
4.4.2. 6-Bromo-3-(trimethylsilylethynyl)quinolin-4(1H)-one (8). Rf
0.60 (CH2Cl2/MeOH 9/1); mp 260e261 ꢀC; 1H NMR (400 MHz,
4.5.2. N-(Adamantan-1-yl)-6-bromo-1-methylquinolin-4(1H)-one-
(CD3)2SO):
d
8.32 (s, 1H), 8.16 (d, Jmeta¼4.0 Hz, 1H), 7.82 (dd, Jor-
3-carboxamide (7i). Rf 0.30 (CH2Cl2/MeOH 97/3); mp 191e192 ꢀC;
¼8.0 Hz, Jmeta¼4.0 Hz, 1H), 7.55 (d, Jortho¼8.0 Hz, 1H), 0.21 (s, 9H);
tho
1H NMR (200 MHz, CDCl3):
d 10.87 (s, 1H), 8.77 (s, 1H), 8.64 (d,
13C NMR (100 MHz, (CD3)2SO):
d
222.2, 174.0, 144.1, 137.8, 134.6,
J¼3.7 Hz, 1H), 7.76e7.63 (m, 1H), 7.3 (d, J¼11.2 Hz, 1H), 3.93 (s, 3H),
126.9, 126.2, 121.3, 116.6, 104.3, 101.1, 96.0; IR (CHCl3):
n 2158,
2.90e2.18 (m, 9H), 1.78e1.19 (m, 6H); 13C NMR (100 MHz, CDCl3):
1609 cmꢁ1; MS: m/z (Mþþ1) 321. Anal. Calcd for C14H14BrNOSi: C,
d 175.4, 163.1, 148.3, 138.6, 135.7, 134.7, 129.8, 119.1, 117.7, 113.5, 46.1,
52.50; H, 4.41; N, 4.37; found: C, 52.81; H, 4.49; N, 4.22.
42.6, 41.8, 41.6, 41.5, 37.2, 36.5, 36.4, 30.0, 29.5, 29.4; IR (Nujol): n
1661, 1634 cmꢁ1
C21H23BrN2O2: C, 60.73; H, 5.58; N, 6.74; found: C, 61.06; H, 5.68; N,
6.51.
;
MS: m/z (Mþþ1) 416. Anal. Calcd for
4.4.3. 1-Methyl-3-phenyl-6-(phenylethynyl)quinolin-4(1H)-one
(1h). Rf 0.60 (CH2Cl2/MeOH 98/2); mp 202e203 ꢀC; 1H NMR
(400 MHz, CDCl3):
J¼8.0 Hz, 2H), 7.55 (s, 1H), 7.49e7.48 (m, 2H), 7.36e7.23 (m, 7H),
3.74 (s, 3H); 13C NMR (100 MHz, CDCl3):
175.2, 142.6, 139.4, 135.2,
d
8.61 (s, 1H), 7.65 (d, J¼8.0 Hz, 1H), 7.59 (d,
4.5.3. N-(Adamantan-1-yl)-6-bromo-1-pentylquinolin-4(1H)-one-3-
d
carboxamide (7k). Rf 0.64 (AcOEt/hexanes 1/1); mp 150e151 ꢀC; 1H
134.6, 131.7,130.9,128.6, 128.4, 128.3,127.2,123.1,122.5,118.8,115.5,
NMR (400 MHz, CDCl3):
d
9.79 (s, 1H), 8.71 (s, 1H), 8.63 (d, J¼2.0 Hz,
90.1, 88.7, 40.8; IR (CHCl3):
n
2145, 1631 cmꢁ1; MS: m/z (Mþþ1) 336.
1H), 7.77 (dd, Jortho¼8.9 Hz, Jmeta¼2.1 Hz, 1H), 7.37 (d, J¼8.9 Hz, 1H),
4.18 (t, J¼7.4 Hz, 2H), 2.2e2.1 (m, 9H), 1.9e1.8 (m, 2H), 1.7e1.6 (m,
6H), 1.32e1.35 (m, 2H), 1.23 (t, J¼6.9 Hz, 2H), 0.89 (t, J¼6.8 Hz, 3H);
Anal. Calcd for C24H17NO: C, 85.94; H, 5.11; N, 4.18; found: C, 85.55;
H, 5.02; N, 3.89.
13C NMR (100 MHz, CDCl3):
d 177.5, 158.9, 144.1, 143.1, 138.3, 134.2,
4.4.4. 1-Methyl-6-(phenylethynyl)-3-(trimethylsilylethynyl)quinolin-
129.3, 116.2, 112.0, 111.8, 46.2, 41.2, 37.8, 36.8, 29.7, 28.1, 27.8, 26.1,
4(1H)-one (1k). Rf 0.62 (CH2Cl2/MeOH, 98/2); mp 210e211 ꢀC; 1H
22.5, 14.1; IR (CHCl3):
n
1660, 1632 cmꢁ1; MS: m/z (Mþþ1) 472.

C. Mugnaini et al. / Tetrahedron 67 (2011) 5776e5783
5783
Anal. Calcd for C25H31BrN2O2: C, 63.69; H, 6.63; N, 5.94; found: C,
63.46; H, 6.50; N, 5.65.
m/z (Mþþ1) 474. Anal. Calcd for C28H25ClN2O3: C, 71.10; H, 5.33; N,
5.92; found: C, 71.41; H, 5.23; N, 5.70.
4.5.4. N3-(Adamantan-1-yl)-1-methyl-N6-phenylquinolin-4(1H)-
Acknowledgements
one-3,6-dicarboxamide (1m). Rf 0.54 (CH2Cl2/MeOH 98/2); mp
172e173 ꢀC; 1H NMR (200 MHz, CDCl3):
d 9.90 (s, 1H), 8.72 (s, 2H),
We thank Professors Maurizio Taddei and Elena Petricci, Dept.
Farmaco Chimico Tecnologico, University of Siena, for kindly pro-
viding access to MW equipment for aminocarbonylation reactions
using gaseous carbon monoxide and for helpful discussions. Fi-
nancial support from Siena Biotech S.p.A., Siena (Italy) is gratefully
acknowledged.
8.52e8.48 (m, 1H), 7.77e7.69 (m, 1H), 7.52e7.45 (m, 5H), 5.27 (s,
1H), 3.91 (s, 3H), 2.15e1.88 (m, 9H), 1.77e1.64 (m, 6H); 13C NMR
(100 MHz, CDCl3):
d 176.8, 169.3, 163.6, 148.1, 144.0, 139.9, 136.0,
132.8, 128.9, 127.8, 127.2, 125.1, 124.1, 122.5, 119.9, 115.8, 113.0, 51.9,
51.7, 41.8, 41.6, 41.4, 36.6, 36.4, 29.7, 29.6, 29.4, 24.7; IR (CHCl3):
n
1659, 1638 cmꢁ1; MS: m/z (Mþþ1) 456. Anal. Calcd for C28H29N3O3:
C, 73.82; H, 6.42; N, 9.22; found: C, 74.13; H, 6.30; N, 8.91.
Supplementary data
Synthetic procedures and spectroscopic data for compounds
2e4, and elemental analyses data for all new compounds. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2011.05.134.
4.6. Synthesis of 6-bromo-1-ethyl-3-[(morpholin-4-yl)
carbonyl]-quinolin-4(1H)-one (7j)
A microwave vial was charged with 4c (18.9 mg, 0.05 mmol),
morpholine (4.6
mL, 0.05 mmol), DBU (23 mL, 0.15 mmol), DMF
References and notes
(100 L) and 10% Pd/C (1 mg, 0.001 mmol). The reaction mixture
m
was irradiated with microwaves at 100 ꢀC under a CO pressure of
130 psi for 2ꢂ5 min. After cooling, the mixture was diluted with
ethyl acetate, filtered on Celite and washed with 1 N HCl, then with
brine. Removal of solvents gave a residue, which was purified by
chromatography on silica gel (CH2Cl2/MeOH 94/6) to yield 7j as
a clear oil (7 mg, 30%). Rf 0.53 (CH2Cl2/MeOH 93/7); 1H NMR
€
1. Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med. Chem. 2006,
49, 4568.
2. DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Comb.
Chem. High Throughput Screening 2004, 7, 473.
3. Mugnaini, C.; Pasquini, S.; Corelli, F. Curr. Med. Chem. 2009, 16, 1746.
4. Jin, G. H.; Ha, S. K.; Park, H. M.; Kang, B.; Kim, S. Y.; Kim, H.-D.; Ryu, J.-H.; Jeon, R.
Bioorg. Med. Chem. Lett. 2008, 18, 4092.
5. Klampfer, L. Curr. Cancer Drug Targets 2006, 6, 107.
6. Lager, E.; Andersson, P.; Nilsson, J.; Pettersson, I.; Nielsen, E. O.; Nielsen, M.;
Sterner, O.; Lilijefors, T. J. Med. Chem. 2006, 49, 2526.
7. Park, C.-H.; Lee, J.; Jung, H. Y.; Kim, M. J.; Lim, S. H.; Yeo, H. T.; Choi, E. C.; Yoon,
E. J.; Kim, K. W.; Cha, J. H.; Kim, S.-H.; Chang, D.-J.; Kwon, D.-Y.; Li, F.; Suh, Y.-G.
Bioorg. Med. Chem. 2007, 15, 6517.
8. Lucero, B. d’A.; Gomes, C. R. B.; Frugulhetti, I. C. d. P. P.; Faro, L. V.; Alvarenga, L.;
de Souza, M. C. B. V.; de Souza, T. M. L.; Ferreira, V. F. Bioorg. Med. Chem. Lett.
2006, 16, 1010.
9. Massari, S.; Daelemans, D.; Barreca, M. L.; Knezevich, A.; Sabatini, S.; Cecchetti,
V.; Marcello, A.; Pannecouque, C.; Tabarrini, O. J. Med. Chem. 2010, 53, 641 and
references cited therein.
(200 MHz, CDCl3):
Jortho¼9.0 Hz, Jmeta¼2.3 Hz, 1H), 7.33 (d, J¼8.9 Hz, 1H), 4.25e4.11 (m,
2H), 3.76 (s, 8H), 1.51 (m, 3H); 13C NMR (100 MHz, CDCl3):
172.2,
165.9, 146.1, 137.9, 135.8, 130.5, 129.4, 118.9, 118.5, 117.9, 67.5, 67.0,
d
8.57 (d, J¼2.3 Hz, 1H), 8.03 (s, 1H), 7.75 (dd,
d
49.0, 48.3, 43.3, 14.7; IR (CHCl3):
n
1631, 1620 cmꢁ1; MS: m/z
(Mþþ1) 366. Anal. Calcd for C16H17BrN2O3: C, 52.62; H, 4.69; N,
7.67; found: C, 52.92; H, 4.59; N, 7.79.
10. Boteva, A. A.; Krasnykh, O. P. Chem. Heterocycl. Compd. 2009, 45, 757; Khim.
Geterotsikl. Soedin. 2009, 963.
11. Pasquini, S.; Mugnaini, C.; Tintori, C.; Botta, M.; Trejos, A.; Arvela, R. K.; Larhed,
M.; Vitvrouw, M.; Michiels, M.; Christ, F.; Debyser, Z.; Corelli, F. J. Med. Chem.
2008, 51, 5125.
12. Pasquini, S.; Ligresti, A.; Mugnaini, C.; Semeraro, T.; Cicione, L.; De Rosa, M.;
Guida, F.; Luongo, L.; De Chiaro, M.; Cascio, M. G.; Bolognini, D.; Marini, P.;
Pertwee, R.; Maione, S.; Di Marzo, V.; Corelli, F. J. Med. Chem. 2010, 53, 5915 and
references cited therein.
4.7. Synthesis of 3-(4-chlorophenyl)-1-cyclopropylmethyl-N-
(4-methoxybenzyl)quinolin-4(1H)-one-6-carboxamide (1i)
A microwave vial was charged with 7f (19.4 mg, 0.05 mmol), 4-
methoxybenzylamine (6.6
0.15 mmol), dry THF (200
m
L, 0.05 mmol), DIPEA (26
mL,
mL) and Pd(PPh3)2Cl2 (1.78 mg,
0.0025 mmol). The reaction mixture was irradiated with micro-
waves at 130 ꢀC under a CO pressure of 120 psi for 2ꢂ20 min. After
cooling, the mixture was diluted with ethyl acetate, filtered on
Celite and washed with 1 N HCl, then with brine. Removal of sol-
vents gave a residue, which was chromatographed on silica gel
(CH2Cl2/MeOH 98/2) to give 10.3 mg (53%) of the starting material
7f and subsequently 7.1 mg (30%) of the title compound 1i as
a colourless oil. Rf 0.30 (CH2Cl2/MeOH 98/2); 1H NMR (400 MHz,
13. Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
14. For general references on metal-catalyzed reactions, see: Slagt, V. F.; de Vries,
A. H. M.; de Vries, J. G.; Kellogg, R. M. Org. Process Res. Dev. 2010, 14, 30.
15. For examples of recent applications of palladium-catalyzed coupling reactions
in the pharmaceutical, agrochemical, and fine chemical industries, see: Tor-
borg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027.
16. Schofield, K.; Swain, T. J. Chem. Soc. 1950, 384.
17. Heindel, N. D.; Kennewell, P. D.; Fish, V. B. J. Heterocycl. Chem. 1969, 6, 77.
18. Renault, J.; Mailliet, P.; Renault, S.; Berlot, J. Synthesis 1977, 865.
19. Almeida, I. S.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2010, 462.
20. Zhang, X.; Liu, A.; Chen, W. Org. Lett. 2008, 10, 3849.
CDCl3):
d
8.74 (d, J¼2.0 Hz, 1H), 8.27 (dd, Jortho¼8.0 Hz, Jmeta¼2.0 Hz,
21. Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett. 2006, 47, 7317.
22. Glasnov, T. N.; Kappe, C. O. QSAR Comb. Sci. 2007, 26, 1261.
23. Babudri, F.; De Palma, D.; Farinola, G. M.; Ragni, R.; Naso, F. Synthesis 2008, 1227.
1H), 7.73 (s, 1H), 7.57e7.52 (m, 3H), 7.32 (d, J¼8.0 Hz, 2H), 7.23e7.19
(m, 2H), 6.80e6.78 (m, 2H), 4.52 (d, J¼4.0 Hz, 2H), 4.01 (d, J¼4.0 Hz,
2H), 3.73 (s, 3H), 1.31e1.28 (m, 1H), 0.71e0.67 (m, 2H), 0.41e0.39
€
ꢁ
24. Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6, 1097.
(m, 2H); 13C NMR (100 MHz, CDCl3):
d
175.7, 166.1, 159.3, 141.9,
141.4,133.7,132.3,130.1,129.7,129.6,128.8,126.6,125.3, 116.2,114.4,
57.8, 55.6, 44.0, 29.9, 10.5, 4.8; IR (CHCl3):
1629, 1610 cmꢁ1; MS:
25. Ma, S.; Wu, B.; Jiang, X. J. Org. Chem. 2005, 70, 2588.
€
26. Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114.
€
27. Wu, X.; Ronn, R.; Gossas, T.; Larhed, M. J. Org. Chem. 2005, 70, 3094.
n
28. Salvadori, J.; Balducci, E.; Zaza, S.;Petricci, E.;Taddei, M. J. Org. Chem. 2010, 75,1841.