A general copper powder-catalyzed ullmann-type reaction of 3-halo-4(1 H)-quinolones with various nitrogen-containing nucleophiles

Article abstract of DOI:10.1021/jo200680j

3-(N-Substituted) 4(1H)-quinolinones were synthesized using the copper-catalyzed Ullmann C-N bond forming strategy in moderate to quantitative yields. Starting from 3-halo-4(1H)-quinolones, various nucleophiles including amides, lactams, sulfonamides and NH-containing azoles have been used successfully. In all cases, the reactions take place rapidly in toluene and proceed by using copper powder as a catalyst, DMEDA as a ligand and K ₂CO₃ as a base. In addition, other related heterocycles such as 3-bromoquinolin-2(1H)-ones, 3-bromocoumarin, and 3,5-dibromo-2-pyridone show good to very high reactivity with various nucleophiles under our Cu/DMEDA catalyst system.

Full text of DOI:10.1021/jo200680j

ARTICLE
pubs.acs.org/joc
A General Copper Powder-Catalyzed Ullmann-Type Reaction of
3-Halo-4(1H)-quinolones With Various Nitrogen-Containing
Nucleophiles
Davide Audisio, Samir Messaoudi,* Jean-Franc-ois Peyrat, Jean-Daniel Brion, and Mou^ad Alami*
1Univ Paris-Sud, 2CNRS, BioCIS UMR 8076, Laboratoire de Chimie Thꢀerapeutique, Facultꢀe de Pharmacie, 5 rue J.-B. Clꢀement,
Ch^atenay-Malabry, F-92296, France
S Supporting Information
b
ABSTRACT: 3-(N-Substituted) 4(1H)-quinolinones were
synthesized using the copper-catalyzed Ullmann CꢀN bond
forming strategy in moderate to quantitative yields. Starting
from 3-halo-4(1H)-quinolones, various nucleophiles including
amides, lactams, sulfonamides and NH-containing azoles have
been used successfully. In all cases, the reactions take place
rapidly in toluene and proceed by using copper powder as a
catalyst, DMEDA as a ligand and K2CO3 as a base. In addition,
other related heterocycles such as 3-bromoquinolin-2(1H)-
ones, 3-bromocoumarin, and 3,5-dibromo-2-pyridone show
good to very high reactivity with various nucleophiles under our Cu/DMEDA catalyst system.
3-bromocoumarins9 with various nitrogen nucleophiles,10 in-
1. INTRODUCTION
cluding amines, amides, sulfonamides, carbamates, ureas, and
azide anion. As part of our continuing effort at the construction of
3-Substituted 4(1H)-quinolinones represent an important
class of heteroaromatic compounds, which have attracted a lot
heterocycles via transition metal-catalyzed reactions, combined
of attention because of their pharmacological properties.1 In
with our interest in discovering new hsp90 inhibitors,11 we
addition, these heterocyclic structures are common scaffolds
decided to explore the ability of the 3-haloquinolin-4(1H)-ones
found in various natural products.2 One of the most important
to participate in metal-catalyzed CꢀN cross-coupling reactions
subfamilies of 4(1H)-quinolinones is 3-aminoquinolin-4(1H)-
with various nitrogen nucleophiles. From a synthetic viewpoint,
ones, whose derivatives show promising biological activities,
this coupling should be the shortest and most efficient route to
including cannabinoid type 2 receptor agonists3 and hepatite C
3-(N-substituted)-quinolin-4(1H)-ones for the purpose of med-
icinal chemistry screening programs. To the best of our knowl-
edge, there is no report describing the formation of 3-(N-
substitued)-quinolin-4(1H)-ones using this idea.
antivirals.4 While these derivatives clearly hold great potential in
organic synthesis, a careful examination of the literature reveals
lack methods for their preparation. Most routes to prepare
3-aminoquinolin-4(1H)-ones involve from 4(1H)-quinolinone-
3-carboxylic acid derivatives a Curtius reaction using diphenyl-
Initial studies focused on the palladium-catalyzed coupling of
3-iodoquinolinone 1a with 4-methoxybenzamide 2a under our
phosphorylazide followed by further N-functionalization,3 or the
previous conditions (Pd(OAc)2/Xantphos, Cs2CO3, dioxane,
sequential nitro-decarboxylation/reduction processes.5 Alterna-
100 °C).10a However, this transformation was inefficient to
tive route consists on the cyclization of a suitable phenacyl
anthranilamide in the presence of (poly)phosphoric acid under
provide 3a, and all our attempts to react 1a with 2a using various
combinations of palladium/ligand/base mixtures resulted, un-
extremely harsh conditions.6 All these multistep procedures,
fortunately, in unsatisfactory results (data not shown). The
however, are often moderate to low yielding, difficult to handle
for large-scale operations, the variety of substrates is narrow, and
highest yield was achieved by using Pd(OH)2/C as the catalyst,
and Xantphos as the ligand in dioxane at 140 °C. Under these
thus finds limited application in library synthesis. Therefore, the
conditions, the targeted 3-carboxamide-4-quinolinone 3a was
search for new selective, and simple procedures, as well as
diversity oriented reactions such as metal-catalyzed couplings,
presents an interesting challenge.
formed in a moderate 49% yield (Scheme 1).
Difficulties in obtaining 4-quinolinones 3a in good yield under
palladium-catalysis led us to explore alterantive procedures. We felt
In an ongoing medicinal chemistry program7 directed toward
that the copper-based protocols may be readily extended to the
hsp90, an exciting new target in cancer drug discovery,8 we
reported the synthesis of 3-(N-substituted)-quinolin-2(1H)-
ones and coumarins based on the metal-catalyzed CꢀN
Received: April 1, 2011
Published: April 27, 2011
bond coupling reaction of 3-bromoquinolin-2(1H)-ones and
r
2011 American Chemical Society
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Scheme 1. Palladium-Catalyzed Amidation of 3-Iodo-4-qui-
nolinone 1a
Figure 1. 3-Halo-4-quinolinones 1 used in this study.
2. RESULTS AND DISCUSSION
Very recently, we have developed the copper(0) powder
catalyzed C(sp2)-NH2 bond formation to provides 3-aminoquino-
lin-2(1H)-one and 3-aminocoumarins as well as anilines.10c Thus, it
was a natural extension for us to use initially this air-stable and
inexpensive Cu(0) powder for preparing 3-carboxamide-4-quinoli-
none 3a through the coupling of 1a (1 mmol) with 2a (1.2 mmol) as
a model reaction. As summarized in Table 1, we found in this study
that the nature of the base and the ligand were crucial to the outcome
of the coupling. For the optimization process, we first screened a
variety of bases (1.5 equiv) using Cu(0) powder (10 mol %) as the
catalyst, and N,N0-dimethylethylenediamine (DMEDA, 20 mol %) as
the ligand in toluene at 135 °C. It was observed that the reaction
was dramatically facilitated when using K2CO3 or Cs2CO3, as the
bases, thus providing the desired 4-quinolinone 3a in excellent yields
(87ꢀ96%, entries 4 and 5). Other bases such as Na2CO3, K3PO4,
and Et3N were less effective (entries 1ꢀ3). We then examined a
variety of ligands. Changing DMEDA to the (()-trans-cyclohexane-
1,2-diamine-based ligand L3 also led to total conversion although the
yield of 3a was slightly lower (entry 7). The use of other ligands such
as TMEDA, 1,10-phenanthroline, L-proline or ethyl 2-oxocyclohex-
anecarboxylate, however, induced a lowering of the conversion rate
(entries 6 and 8ꢀ10). It is interesting to note that in the coupling of
1a with 2a, the source of copper used has no influence on the reaction
rate, since CuSO4, CuI, CuBr and CuTC (entries 11ꢀ14) gave
similar results than that of Cu(0) powder (entry 5). In summary, the
best conditions were found to require 1a (1 equiv), 2a (1.2 equiv),
Cu powder (10 mol %), DMEDA (20 mol %), K2CO3 (1.5 equiv),
toluene in a sealed tube at 135 °C for 1 h (entry 5).
Table 1. Optimization Coupling Reaction of 1a with Amide
2a under Various Conditionsa
entry
[Cu]
Cu
ligand
base
convb (%)
yieldc (%)
1
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
L2
Na2CO3
K3PO4
Et3N
21
24
nd
nd
nd
87
96d
nd
90
nd
nd
nd
94
94
93
91
2
Cu
3
Cu
15
4
Cu
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
100
10
5
Cu
6
Cu
7
Cu
L3
100
28
8
Cu
L4
With a viable coupling procedure in hand, attention was
turned to the generality of the process, and the couplings of
structurally diverse nucleophiles with some 3-halo-4-quinoli-
nones 113 were studied (Figure 1).
9
Cu
L5
21
10
11
12
13
14
Cu
L6
10
CuSO4
CuI
CuBr
CuTC
DMEDA
DMEDA
DMEDA
DMEDA
100
100
100
100
Results summarized in Table 2, show that the optimized
conditions described above proved to be general for the coupling
with a large variety of nucleophiles. The coupling was found to be
compatible with primary substituted (hetero)aromatic and aliphatic
amides providing the corresponding coupling products 3aꢀl in
good to excellent yields. Interestingly, product 3d revealed an
excellent chemical selectivity at benzamide over aniline, which could
enjoy further metal-catalyzed fuctionalization processes. Although
the yield of 3d was moderate, no compounds resulting from the
coupling at the aniline, neither the disubstitued product have been
isolated. One can note that compound 3i which was obtained in a
a Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Cu] (10 mol %),
ligand (20 mol %), base (1.5 equiv) in toluene were heated in a sealed
Schlenk tube at 135 °C. b Conversion was determined by 1H NMR on
the crude reaction mixture and is based on remaining 1a. c Isolated yields
of 3a. d For control experiments, no conversion at all was observed in the
absence of ligand or Cu(0) and in the absence of Cu(0) and ligand.
83% yield, may be regarded as an analogue of DH4TCNA,11b
a
synthesis of 3-carboxamide-4-quinolinone derivatives 3. Recently,
copper has emerged as a promising alternative as a catalyst for direct
CꢀN bond forming reactions due to their low cost, toxicity, and
offer attractive industrial possibilities in terms of sustainable
chemistry.12 Herein, we report on a copper catalyst system and
reaction conditions that allow, for the first time, the cross-coupling
of N-containing nitrogen nucleophile with 3-haloquinolin-4(1H)-
ones. The reaction proceeds rapidly under relatively mild conditions
providing direct access to various 3-(N-substituted)-quinolin-
4(1H)-ones in good to excellent yields.
potent hsp90 inhibitor. The reaction was also effective with cyclic
amides14 providing the corresponding lactames Nꢀcontaining
quinolinones 3m and 3n in excellent 89% and 97% yields, respec-
tively. Finally, CꢀN bond forming reaction was also studied with
the less nucleophilic alkyl- or arylsulfonamides. These substrates
were found to be suitable nucleophiles for the coupling reaction,
although a longer reaction time were required to obtain total
conversion, and in most cases, satisfactory yields of coupling
products 3o,p were obtained.
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Table 2. Copper-Catalyzed Amidation of 4-Haloquinolinones 1: Synthesis of Functionalized 3-(N-Substitued) aminoquinoli-
nones 3.a
a Reactions of 1 (1.0 mmol) with amide/lactam/sulfonamide (1.2 mmol) were performed in a sealed Schlenk tube at 135 °C in toluene (2 mL) by using
Cu (10 mol %), DMEDA (20 mol %) and K2CO3 (1.5 mmol). b Isolated yields. c A 10% yield of the dehalogenated quinolinone was isolated.
The development of chemistry that could emanate from a single
method for each of the major classes of nitrogen nucleophiles has
been seriously inhibited so far. In an endeavor to expand the scope of
the methodology, we found that our new catalytic system was also
suitable for π-electron-rich nitrogen-containing heterocycles (e.g.,
indoles, pyrroles, azaindoles, indazoles, imidazoles...; Table 3) despite
the fact that the reaction require longer time to total completion.
Several interesting features are apparent from the results in
Table 3. The reaction works well with electron-neutral, electron-
rich and electron-deficient indoles to give the corresponding pro-
ducts in satisfactory to excellent yields (4aꢀe). Additionally, it was
found that chlorine atom at C-5 position of the indole was tolerated,
yielding 4e, which may be useful for further metal-catalyzed fuctio-
nalization processes.15 As with indole, other nitrogen-containing
heterocycles, including 7-azaindole, pyrrole, benzimidazole and
imidazoles were tolerated under the reaction conditions providing
4f, 4i, 4h and 4j in good yields. Extending this chemistry to include
indazoles as substrates proved to be quite successful. Thus, the
reaction of iodoquinolinone 1c with indazole was readily accom-
plished, and excellent regioselectivity for the N-1 arylation product
4g was observed.16
Motivated by these results, we then examined under our
optimized conditions the efficiency of our catalytic system on the
coupling of various nitrogen nucleophiles with other electrophilic
coupling partners, such as 3-bromoquinolin-2(1H)-ones 5aꢀc,
3-bromocoumarin 5d, and 3,5-dibromo-2-pyridone 5e (Figure 2).
As summarized in Table 4, these electrophilic substrates 5 efficiently
undergo the coupling reaction with various nucleophiles under the
catalytic system Cu/DMEDA, providing the corresponding N-cou-
pling products in yield ranging from 41 to 98%. The representative
examples depicted in Table 4 clearly demonstrated the generality of
this reaction.
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Table 3. Copper-Catalyzed CꢀN Coupling of 4-Haloquinolinones 1 with NH-Containing Azolesa
a Reactions of 1 (1.0 mmol) with NH-containing azoles (1.2 mmol) were performed in a sealed Schlenk tube at 135 °C in toluene (2 mL) by using Cu
(10 mol %), DMEDA (20 mol %) and K2CO3 (1.5 mmol). b Isolated yields. c Yield calculated by NMR.
In addition, under our optimal conditions, the reaction
selectivity was investigated with substrates 5c and 5e containing
two carbonꢀbromine bonds. The amination proceeded at the more
activated C-3 position and yielded the monoaminated products
6dꢀg in satisfactory yields (42ꢀ68%), despite the fact that the
reaction conditions had never been optimized. One can note that
compound 6d which was obtained in a 65% yield may be regarded as
an analogue of 6BrCaQ, a potent hsp90 inhibitor recently identified in
our laboratory.11j Finally, a comparative study with 3-bromocoumarin
5d gave a slight reduction in yield of 6h (41%) in comparaison to the
result obtained by palladium catalysis, as we previously reported.10a
Figure 2. Other electrophilic coupling partners 5aꢀe used in this study.
heterocycles was demonstrated by coupling diverses 3-bromoqui-
nolin-2(1H)-ones, 3-bromocoumarin and 3,5-dibromo-2-pyridone
with various nucleophiles under our Cu/DMEDA catalyst system.
Owing to their practical advantages and low environmental impact,
we believe that the reaction described here could be an attractive
alternative for the preparation of potentially bioactive compounds.
3. CONCLUSION
In conclusion, we have demonstrated that the catalytic system
used allows the first general CꢀN bond forming reaction between
3-haloquinolin-4(1H)-ones and various nucleophiles including
amides, lactams, sulphonamides and N-containing heterocycles.
For the first time, the CꢀN bond was formed directly by using
the inexpensive copper powder as the catalyst, DMEDA as the ligand
and toluene as the solvent. Consequently, various 3-(N-substituted)
4(1H)-quinolinones were prepared in good to excellent yields. In
addition, expanding the scope of the method to other related
4. EXPERIMENTAL SECTION
General. The compounds were all identified by usual physical
1
1
methods, that is, H NMR, 13C NMR, IR, elemental analysis. H and
13C NMR spectra were measured in CDCl3 or DMSO-d6 on a 300 MHz
spectrometer. 1H chemical shifts are reported in ppm from an internal
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Table 4. Copper-Catalyzed N-Functionalization of Other Heterocyclic Halides 5a
a Reactions of 1 (1.0 mmol) with amide/lactam/azole (1.2 mmol) were performed in a sealed Schlenk tube at 135 °C in toluene (2 mL) by using Cu (10
mol %), DMEDA (20 mol %) and K2CO3 (1.5 mmol). b Isolated yields.
standard TMS or of residual chloroform (7.27 ppm). The following
abreviation are used: m (multiplet), s (singlet), br s (broad singlet), d
(doublet), t (triplet) dd (doublet of doublet), td (triplet of doublet). 13C
chemical shifts are reported in ppm from the central peak of deuterio-
chloroform (77.14).
Materials. Unless otherwise noted, reagents were commercially
avialble and were used without purification. Rf values refer to TLC on
0.25 mm silica gel plates (60-F254, Merck KGaA). Flash chromatogra-
phy was performed on silica gel 60 (0.040ꢀ0.063 mm, Merck KGaA). IR
spectra were acquired on a FT-IR and are reported in wave numbers
(cm-1). Elemental analyses were performed with a Perkin-Elmer 240
analyzer. Melting points (m.p.) were determined on a capillary melting
point apparatus and were uncorrected.
Starting Materials Synthesis. 3-Iodo-1-methylquinolin-4(1H)-
one (1a). To a suspension of 3-iodoquinolin-4(1H)-one13c,d (3 g, 11.1
mmol, 1.0 equiv) in dry THF (50 mL) was added NaH (670 mg of a 65%
oil dispersion, 16.6 mmol, 1.5 equiv) under argon atmosphere. After 30
min, methyl iodide (700 μL, 16.6 mmol, 1.5 equiv) was added dropwise.
The reaction mixture was stirred for 1.5 h at room temperature, before
being quenched with saturated NaCl aqueous solution and the aqueous
layer extracted with DCM (5 times) and EtOAc (2 times). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated in vacuo. Purification by flash column chromatography on silica
gel yielded the desired product 1a as a light-yellow solid.
Yield 75%, light-yellow solid, mp 196ꢀ198 °C, Rf = 0.50 (CH2Cl2/
MeOH 95:5). IR 3025, 1578, 1545, 1494, 1467, 1430, 1363, 1261, 1166,
1146, 1118, 1079, 1038, 956, 830, 784, 753, 689, 621 cmꢀ1.1H NMR
(300 MHz, CDCl3, δ, ppm): 8.40 (dd, 1H, J1 = 8.1 Hz, J2 = 1.6 Hz), 8.02
(s, 1H), 7.67 (td, 1H, J1 = 8.5 Hz, J2 = 1.6 Hz), 7.42ꢀ7.34 (m, 2H), 3.81
(s, 3H). 13C NMR (75 MHz, CDCl3, δ, ppm): 174.0, 148.3, 140.0,
132.3, 127.6, 124.6, 123.4, 115.4, 80.7, 40.7. MS (ESIþ) m/z: 286.0
(M þ H)þ. Anal. Calcd for C10H8INO (284.97): C 42.13, H 2.83, N
4.91; found: C 42.17, H 2.88, N 4.99.
1.5 equiv) in one portion, under argon atmosphere. After 30 min,
dimethyl sulfate (508 μL, 5.36 mmol, 1.5 equiv) was added dropwise.
The reaction mixture was stirred for 4 h at room temperature, before
being quenched with saturated NaCl aqueous solution and the aqueous
layer extracted with DCM (5 times). The combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography on silica gel yielded the desired product 1b.
Yield 84%, beige solid, mp 234ꢀ236 °C, Rf = 0.54 (CH2Cl2/MeOH:
95/5). IR 3029, 1582, 1548, 1498, 1470, 1364, 1263, 1170, 1150, 1121,
1082, 1039, 957, 843, 785, 754, 691, 619, 584, 573 cmꢀ1. 1H NMR (300
MHz, CDCl3, δ, ppm): 8.48 (dd, 1H, J1 = 8.1 Hz, J2 = 1.1 Hz), 7.93 (s,
1H), 7.69 (td, 1H, J1 = 8.6 Hz, J2 = 1.6 Hz), 7.42 (td, 1H,
J1 = 8.1 Hz, J2 = 0.9 Hz), 7.40 (d, 1H, J = 8.5 Hz), 3.83 (s, 3H). 13C
NMR (75 MHz, DMSO-d6, δ, ppm): 170.8, 145.1, 139.7, 132.1, 125.8,
124.7, 124.2, 116.9, 103.3, 40.0. MS (APCIþ) m/z: 238.0 ([M þ H]þ,
79Br), 240.0 ([M þ H]þ, 81Br). Anal. Calcd for C10H8BrNO (236.98):
C 50.45, H 3.39, N 5.88; found: C 50.48, H 3.41, N 5.90.
1-Benzyl-3-iodoquinolin-4(1H)-one (1c). To a suspension of 3-iodo-
quinolin-4(1H)-one13c (1.8 g, 6.64 mmol, 1.0 equiv) in dry THF (25 mL)
was added NaH (400 mg of a 65% oil dispersion, 9.96 mmol, 1.5 equiv)
under argon atmosphere. After 30 min, benzyl bromide (1.6 mL, 13.3
mmol, 2.0 equiv) was added dropwise. The reaction mixture was stirred for
12 h at room temperature, before being quenched with saturated NaCl
aqueous solution and the aqueous layer extracted with DCM (5 times) and
EtOAc (2 times). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. Purification by flash column chroma-
tography on silica gel yielded the desired product 1c.
Yield 72%, white solid, mp 203ꢀ205 °C, Rf = 0.65 (CH2Cl2/MeOH:
95/5). IR 1615, 1592, 1541, 1484, 1369, 1267, 1228, 831, 758, 739, 688,
620, 590, 572, 560 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.46
(dd, 1H, J1 = 8.1 Hz, J2 = 1.6 Hz), 8.18 (s, 1H), 7.54 (td, 1H, J1 = 8.6 Hz,
J2 = 1.6 Hz), 7.38ꢀ7.28 (m, 5H), 7.15ꢀ7.12 (m, 2H), 5.34 (s, 2H). 13
C
NMR (75 MHz, CDCl3, δ, ppm): 174.1, 148.1, 139.6, 134.6, 132.3,
129.3 (2C), 128.5, 127.9, 126.0 (2C), 124.6, 123.9, 116.1, 81.5, 56.5. MS
(APCIþ) m/z: 362.0 [M þ H]þ. Anal. Calcd for C16H12INO (361): C
53.21, H 3.35, N 3.88; found: C 53.21, H 3.35, N 3.88.
3-Bromo-1-methylquinolin-4(1H)-one (1b). To a suspension of
3-bromoquinolin-4(1H)-one (0.8 g, 3.6 mmol, 1.0 equiv) in dry THF
(15 mL) was added NaH (128 mg of a 65% oil dispersion, 5.36 mmol,
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3-Iodo-2-(4-methoxyphenyl)-1-methylquinolin-4(1H)-one (1d). To
a suspension of 3-iodo-2-(4-methoxyphenyl)quinolin-4(1H)-one17,18
(1.12 g, 3.07 mmol, 1.0 equiv) in dry THF was added NaH (184 mg
of a 65% oil dispersion, 4.60 mmol, 1.5 equiv) in one portion, under
argon atmosphere. After 30 min, methyl iodide (300 μL, 4.60 mmol,
1.5 equiv) was added dropwise. The reaction mixture was stirred for 2 h
at room temperature, before being quenched with saturated NaCl and
the aqueous layer was extracted with EtOAc (3 times). The combined
organic layers were washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. Purification by flash column chromatography on
silica gel yielded the desired product 1d.
Yield 91%, brown solid, mp 189ꢀ191 °C, Rf = 0.63 (c-hexane/
AcOEt: 2/8). IR 2923, 1614, 1591, 1502, 1459, 1391, 1288, 1245, 1178,
1150, 1109, 1077, 1028, 853, 824, 787, 766, 684 cmꢀ1. 1H NMR (400
MHz, CDCl3, δ, ppm): 8.41 (dd, 1H, H5, J1 = 8.0 Hz, J2 = 0.8 Hz), 7.61
(t, 1H, H7, J = 8.4 Hz), 7.46 (d, 1H, H8, J = 8.6 Hz), 7.32 (t, 1H, H6, J =
7.5 Hz), 7.14 (d, 2H, H13, J = 8.6 Hz), 7.02 (d, 2H, H14, J = 8.6 Hz), 3.84
(s, 3H, H16), 3.54 (s, 3H, H11). 13C NMR (100 MHz, CDCl3, δ, ppm):
173.8, 160.2, 155.1, 140.5, 132.3, 131.5, 129.5 (2C), 127.3, 124.1, 122.6
(C10), 115.7, 114.3 (2C), 89.7, 55.2, 39.1. MS (APCIþ) m/z: 392.0
[M þ H]þ. Anal. Calcd for C17H14INO2 (391.01): C 52.19, H 3.61, N
3.58; found: C 52.23, H 3.65, N 3.62.
2.16 mmol, 1.0 equiv) in dry THF at room temperature was added
MPHT19 (1.9 g, 4.3 mmol, 2.0 equiv). The reaction mixture was stirred
for 2 h at 80 °C, before being quenched with saturated Na2S2O3 aqueous
solution. The mixture was left 12 h at r.t. and the solid formed was
filtered and washed with c-hexane to yield the desired product 1g as a
white solid (460 mg, 1.74 mmol, 81%).
Yield 81%, white solid, mp 207ꢀ209 °C, Rf = 0.30 (CH2Cl2/MeOH:
95/5). IR 1616, 1572, 1541, 1503, 1468, 1422, 1257, 1162, 1081, 973, 812,
768, 689, 619 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.41 (dd, 1H,
J1 = 8.1 Hz, J2 = 1.4 Hz), 7.61 (ddd, 1H, J1 = 8.5 Hz, J2 = 7.1, J3 = 1.5 Hz),
7.37ꢀ7.32 (m, 1H), 7.25 (d, 1H, J = 8.3 Hz), 4.37 (t, 2H, J = 7.5 Hz),
3.28 (t, 2H, J = 7.9 Hz), 2.41 (q, 2H, J = 7.7 Hz). 13C NMR (75 MHz,
CDCl3, δ, ppm): 172.4, 154.2, 137.5, 131.9, 127.3, 124.3, 123.9, 115.4,
101.8, 51.9, 34.3, 20.4. MS (ESþ) m/z: 286.0 ([M þ Na]þ, 79Br), 288.0
([M þ Na]þ, 81Br). Anal. Calcd for C12H10BrNO (262.99): C 54.57, H
3.82, N 5.30; found: C 54.61, H 3.85, N 5.33.
General Procedure for Cu-Catalyzed Couplings of 3-Haloquino-
lones with Various Nucleophiles: Amides, Lactams, Sulfonamides, NH-
Containing Azoles. A flame-dried resealable Schlenk tube was charged
with Cu powder (10 mol %) the solid reactant(s) (1.0 mmol of the
haloquinolone, 1.2 mmol of the amide/lactam/sulfonamide/azole) and
K2CO3 (1.5 mmol). The Schlenk tube was capped with a rubber septum,
evacuated and backfilled with argon; this evacuation/backfill sequence
was repeated one additional time. DMEDA (20 mol %), the liquid
reactant(s) and toluene (2 mL) were added through the septum. The
septum was replaced with a Teflon screwcap. The Schlenk tube was
sealed, and the mixture was stirred at 135 °C for the indicated time. The
resulting suspension was cooled to room temperature and filtred
through Celite eluting with ethyl acetate, and the inorganic salts were
removed. The filtrate was concentrated and purification of the residue by
silica gel column chromatography gave the desired product.
4-Methoxy-N-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl) benzamide
(3a). The reaction was carried out with 1a (100 mg, 0.35 mmol) for 1 h
according to the general procedure to obtain 3a (104 mg, 0.34 mmol).
Yield 96%, white solid, mp 158ꢀ160 °C, Rf =0.25(CH2Cl2/AcOEt: 8/2).
IR 1633, 1585, 1543, 1493, 1474, 1401, 1309, 1246, 1177, 1116, 1024, 890,
857, 746, 697, 623 cmꢀ1.1H NMR (300 MHz, CDCl3,δ,ppm):9.34(s,1H),
9.18 (s, 1H), 8.51 (d, 1H, J= 8.1 Hz), 7.93 (d, 2H, J= 8.4 Hz), 7.69 (t, 1H, J=
7.8 Hz), 7.46 (d, 1H, J = 8.7 Hz), 7.40 (t, 1H, J = 7.5 Hz), 6.98 (d, 2H, J = 8.4
Hz), 3.91 (s, 3H), 3.87 (s, 3H). 13CNMR (75 MHz, CDCl3, δ, ppm): 170.1,
164.9, 162.5, 138.6, 132.4, 131.9, 129.0 (2C), 126.7, 126.4, 123.7, 123.1, 122.6,
115.3, 113.9 (2C), 55.4, 41.2. MS (APCIþ) m/z: 309.0 [M þ H]þ. Anal.
Calcd.for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 69.83; H, 5.38;
N, 8.87. Anal. Calcd for C18H16N2O3 (308.12): C 70.12, H 5.23, N 9.09;
found: C 70.17, H 5.27, N 9.11.
ꢀ
1-Heptyl-3-iodoquinolein-4(1H)-one (1e). To a suspension of 3-iodo-
quinolin-4(1H)-one (1 g, 3.69 mmol, 1.0 equiv) in dry THF (20 mL) was
added NaH (440 mg of a 65% oil dispersion, 11.0 mmol, 3.0 equiv) under
argon atmosphere. After 30 min, 7-iodoheptane (3.0 μL, 18.4 mmol, 5.0
equiv) was added dropwise. The reaction mixture was stirred for 24 h at
room temperature, before being quenched with saturated NaCl aqueous
solution and the aqueous layer extracted with DCM (3 times). The
combined organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. Purification by flash column chromatography on silica gel yielded
the desired product 1e.
Yield 82%, brown solid, mp 83ꢀ85 °C, Rf = 0.65 (CH2Cl2/MeOH:
95/5). IR 3031, 2915, 2857, 1613, 1585, 1543, 1487, 1469, 1414, 1384, 1366,
1262, 1234, 1192, 1170, 1138, 1082, 1052, 947, 829, 803, 756, 728, 688,
626 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.47 (dd, 1H, J1 = 8.4 Hz,
J2 = 1.6 Hz), 8.06 (s, 1H), 7.66 (td, 1H, J1 = 8.8 Hz, J2 = 1.7 Hz), 7.41ꢀ7.36
(m, 2H), 4.10 (t, 2H, J = 7.5 Hz), 1.85 (q, 2H, J = 7.5 Hz), 1.44ꢀ1.20
(m, 8H), 0.88 (t, 3H, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3, δ, ppm):
173.9, 147.6, 139.1, 132.1, 128.0, 124.4, 123.9, 115.3, 80.9, 53.4, 31.5, 29.0,
28.7, 26.6, 22.5, 14.0. MS (APCIþ) m/z: 370.0 [M þ H]þ. Anal. Calcd for
C9H5INO (269.94): C 40.03, H 1.87, N 5.19; found: C 40.10, H 2.02, N 5.23.
4-Iodo-2,3-dihydropyrrolo[1,2-a]quinolin-5(1H)-one (1f). To a sus-
pension of 2,3-dihydropyrrolo[1,2-a]quinolin-5(1H)-one13c,d (0.2 g,
1.08 mmol, 1.0 equiv) in dry THF at room temperature were added I2
(550 mg, 2.16 mmol, 2.0 equiv) and Na2CO3 (175 mg, 1.62 mmol,
1.5 equiv). The reaction mixture was stirred for 2 h at room temperature,
before being quenched with saturated Na2S2O3 aqueous solution and
the aqueous layer was extracted with EtOAc (2 times) and DCM
(5 times). The combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. Purification by flash column chromatogra-
phy on silica gel yielded the desired product 1f.
ꢀ
4-Methoxy-N-(2-(4-methoxyphenyl)-1-methyl-4-oxo-1,4-dihy-
droquinolin-3-yl)benzamide (3b). The reaction was carried out with
1d (100 mg, 0.26 mmol) for 5 h according to the general procedure to
obtain 3b (69 mg, 0.17 mmol):
Yield 65%, ochre solid, mp 190ꢀ192, °C, Rf = 0.10 (CH2Cl2/AcOEt:
5/5). IR 1670, 1592, 1491, 1289, 1248, 1175, 1025, 841, 761, 687 cmꢀ1
.
1H NMR (300 MHz, CDCl3, δ, ppm): 8.46 (d, 1H, J = 8.0 Hz), 8.12
(bs, 1H), 7.67ꢀ7.7.61 (m, 3H), 7.47ꢀ7.35 (m, 4H), 6.93 (d, 2H, J = 8.5
Hz), 6.69 (d, 2H, J = 8.6 Hz), 3.77 (s, 3H), 3.75 (s, 3H), 3.51 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ, ppm): 174.1, 166.5, 161.8, 160.0, 152.6,
140.8, 132.1, 130.3 (2C), 129.2 (2C), 126.7, 126.0, 125.5, 123.5, 119.0,
116.0, 113.8 (2C), 113.2 (2C), 55.2 (2C), 37.5, one carbon is missed.
MS (APCIþ) m/z: 415.0 [M þ H]þ. Anal. Calcd for C25H22N2O4
(414.16): C 72.45, H 5.35, N 6.76; found: C 72.49, H 5.38, N 6.77.
N-(1-Heptyl-4-oxo-1,4-dihydroquinolin-3-yl)benzamide (3c). The
reaction was carried out with 1e (100 mg, 0.27 mmol) for 1 h according
to the general procedure to obtain 3c (87 mg, 0.24 mmol):
Yield 77%, beige solid, mp 215ꢀ217 °C, Rf = 0.70 (CH2Cl2/MeOH:
95/5). IR 1614, 1590, 1536, 1498, 1420, 1252, 1157, 1078, 970, 766,
687 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.22 (dd, 1H, J1 = 8.1
Hz, J2 = 1.5 Hz), 7.48 (ddd, 1H, J1 = 8.5 Hz, J2 = 7.1 Hz, J3 = 1.6 Hz),
7.24ꢀ7.18 (m, 1H), 7.09 (d, 1H, J = 8.4 Hz), 4.27 (t, 2H, J = 7.6 Hz),
3.10 (t, 2H, J = 7.6 Hz), 2.27 (q, 2H, J = 7.8 Hz). 13C NMR (75 MHz,
CDCl3, δ, ppm): 174.0, 157.1, 137.8, 132.0, 127.4, 124.0, 122.1, 115.2,
78.6, 52.3, 38.1, 20.1. MS (APCIþ) m/z: 312.0 [M þ H]þ. Anal. Calcd
for C12H10INO (310.98): C 46.33, H 3.24, N 4.50; found: C 46.36, H
3.29, N 4.52.
ꢀ
4-Bromo-2,3-dihydropyrrolo[1,2-a]quinolein-5(1H)-one (1g). To a
Yield 88%, beige solid, mp 107ꢀ109 °C, Rf =0.47(CH2Cl2/AcOEt: 8/2).
suspension of 2,3-dihydropyrrolo[1,2-a]quinolin-5(1H)-one, (400 mg,
IR 3362, 2928, 1659, 1630, 1571, 1538, 1472, 1412, 1394, 1321, 1223, 1136,
5000
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The Journal of Organic Chemistry
ARTICLE
1057, 924, 901, 793, 749, 708, 696, 623 cmꢀ1. 1H NMR (300 MHz, CDCl3,
δ, ppm): 9.40 (s, 1H), 9.30 (s, 1H), 8.54 (d, 1H, J = 8.1 Hz), 7.98 (d, 2H, J =
8.1 Hz), 7.68 (t, 1H, J= 8.4 Hz), 7.58ꢀ7.47 (m, 4H), 7.39 (t, 1H, J=7.5Hz),
4.23 (t, 2H, J= 7.6 Hz), 2.00ꢀ1.87 (m, 2H), 1.47ꢀ1.23 (m, 8H) 0.88 (t, 3H,
J =6.7 Hz). 13C NMR(75 MHz, CDCl3, δ, ppm): 170.0, 165.4, 137.9, 134.2,
132.0, 131.9, 131.8, 128.7 (2C), 127.2 (2C), 127.1, 124.1, 123.0, 122.5, 115.4,
54.0, 31.6, 29.1, 28.8, 26.7, 22.5, 14.0. MS (APCIþ) m/z: 363.0 [M þ H]þ.
Anal. Calcd for C23H26N2O2 (362.2) C 76.21, H 7.23, N 7.73; found: C
76.25, H 7.27, N 7.79.
2-Amino-N-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)benzamide (3d).
The reaction was carried out with 1a (100 mg, 0.35 mmol) for
14 h according to the general procedure to obtain 3d (42 mg,
0.14 mmol):
Yield 41%, white solid, mp 155ꢀ157 °C, Rf = 0.33 (CH2Cl2/AcOEt: 8/
2). IR 1610, 1574, 1536, 1473, 1401, 1317, 1225, 1155, 1120, 901, 755,
740 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 9.24 (s, 1H), 9.10 (bs,
1H), 8.50 (d, 1H, J = 7.8 Hz), 7.70ꢀ7.64 (m, 2H), 7.46ꢀ7.37 (m, 2H),
7.28ꢀ7.23 (m, 1H), 6.75ꢀ6.71 (m, 2H) 5.35 (bs, 2H), 3.89 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ, ppm): 170.2, 167.4, 149.0, 138.6, 132.7, 132.1,
131.9, 127.7, 126.6, 123.7, 123.1, 122.6, 117.4, 116.9, 115.4, 115,3, 41.2. MS
(APCIþ) m/z: 294.0 [MþH]þ. Anal. Calcd for C17H15N3O2 (293.12) C
69.61, H 5.15, N 14.33; found: C 69.65, H 5.18, N 14.35.
N-(1-Benzyl-4-oxo-1,4-dihydroquinolin-3-yl)-4-fluorobenzamide
(3e). The reaction was carried out with 1c (100 mg, 0.28 mmol) for 1 h
according to the general procedure to obtain 3e (101 mg, 0.27 mmol):
Yield 98%, violet solid, mp 230ꢀ232 °C, Rf = 0.59 (CH2Cl2/AcOEt:
9/1). IR 1660, 1573, 1542, 1479, 1411, 1313, 1214, 1157, 906, 848, 762,
739, 703 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 9.52 (s, 1H), 9.27
(s, 1H), 8.53 (dd, 1H, J1 = 8.1 Hz, J2 = 1.1 Hz), 8.00 (dd, 2H, J1 = 8.8 Hz,
J2 = 5.2 Hz), 7.58 (ddd, 1H, J1 = 8.5 Hz, J2 = 6.9 Hz, J3 = 1.5 Hz),
7.43ꢀ7.16 (m, 9H), 5.47 (s, 2H). 13C NMR (75 MHz, CDCl3, δ, ppm):
170.4, 165.0 (d, 1C, JCꢀF = 252.6 Hz), 164.3, 138.4, 135.1, 132.5, 132.1,
130.4 (d, 1C, JCꢀF = 2.6 Hz), 129.6, 129.5, 129.2 (2C), 128.3, 126.9,
126.0 (2C), 124.1, 123.3, 122.6, 116.2, 116.0, 115.7, 57.3. MS (ESIþ)
m/z: 373.0 [M þ H]þ. Anal. Calcd for C23H17FN2O2 (372.13) C 74.18,
H 4.60, N 7.52; found: C 74.23, H 4.63, N 7.53.
N-(1-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)thiophene-2-carbo-
xamide (3h). The reaction was carried out with 1a (100 mg, 0.35 mmol)
for 1 h according to the general procedure to obtain 3h (88 mg,
0.31 mmol):
Yield 90%, white solid, mp 215ꢀ217 °C, Rf = 0.47 (CH2Cl2/AcOEt: 8/
2). IR 3279, 1642, 1620, 1565, 1543, 1492, 1474, 1419, 1397, 1316, 1259,
1229, 1163, 1123, 1044, 938, 855, 800, 754, 740, 727, 699, 674. cmꢀ1. 1H
NMR (300 MHz, CDCl3, δ, ppm): 9.28 (s, 1H), 9.13 (bs, 1H), 8.51 (dd,
1H, J1 = 8.2 Hz, J2 = 1.6 Hz), 7.73ꢀ7.68 (m, 2H), 7.55 (dd, 1H, J1 = 5.0 Hz,
J2 = 1.0 Hz), 7.48 (d, 1H, J= 8.7 Hz), 7.42 (ddd, 1H, J1 =7.9Hz, J2 = 7.1Hz,
J3 = 0.8 Hz), 7.14 (dd, 1H, J1 = 4.9 Hz, J2 = 3.8 Hz), 3.92 (s, 3H). 13C NMR
(75 MHz, CDCl3, δ, ppm): 169.8, 160.1, 139.0, 138.7, 132.7, 132.1, 130.9,
128.5, 127.9, 126.8, 123.8, 123.4, 122.2, 115.4, 41.3. MS (APCIþ) m/z:
285.0 [M þ H]þ. Anal. Calcd for C15H12N2O2S (284.06) C 63.36, H 4.25,
N 9.85; found: 63.38, H 4.28, N 9.86.
2,2-Dimethyl-N-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)chroman-
6-carboxamide (3i). The reaction was carried out with 1a (50 mg,
0.17 mmol) for 5 h according to the general procedure to obtain 3i (53
mg, 0.14 mmol):
Yield 83%, light solid, mp 188ꢀ190 °C, Rf = 0.37 (CH2Cl2/AcOEt:
8/2). IR 1653, 1630, 1567, 1536, 1490, 1473, 1403, 1313, 1257, 1155,
1122, 946, 879, 833, 754, 700, 644 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ,
ppm): 9.29 (s, 1H), 9.12 (s, 1H), 8.48 (d, 1H, J = 7.4 Hz), 7.71ꢀ7.61 (m,
3H), 7.42 (d, 1H, J = 8.7 Hz), 7.36 (t, 1H, J = 7.6 Hz), 6.84 (d, 1H, J = 8.9
Hz), 3.87 (s, 3H), 2.83 (t, 2H, J = 6.7 Hz), 1.82 (t, 2H, J = 6.7 Hz), 1.34
(s, 6H). 13C NMR (75 MHz, CDCl3, δ, ppm): 170.0, 165.1, 157.4,
138.6, 132.2, 131.8, 128.9, 126.6 (2C), 125.3, 123.6, 123.0, 122.7, 120.9,
117.4, 115.3, 75.2, 41.1, 32.4, 26.8 (2C), 22.3. MS (APCIþ) m/z: 363.1
[M þ H]þ. Anal. Calcd for C22H22N2O3 (362.16) C 72.91, H 6.12, N
7.73; found: C 72.95, H 6.17, N 7.80.
N-(1-Benzyl-4-oxo-1,4-dihydroquinolin-3-yl)picolinamide (3j).
The reaction was carried out with 1c (100 mg, 0.28 mmol) for 10 h
according to the general procedure to obtain 3j (74 mg, 0.21 mmol):
Yield 75%, white solid, mp 218ꢀ220 °C, Rf = 0.20 (CH2Cl2/AcOEt:
9/1). IR 1660, 1628, 1582, 1539, 1492, 1413, 1323, 1212, 997, 745, 687,
621, 595, 545 cmꢀ1:1H NMR (300 MHz, CDCl3, δ, ppm): 11.01 (s,
1H), 9.55 (s, 1H), 8.70 (ddd, 1H, J1 = 4.7 Hz, J2 = 1.6 Hz, J3 = 0.9 Hz),
8.57 (dd, 1H, J1 = 8.1 Hz, J2 = 1.4 Hz), 8.20 (td, 1H, J1 = 7.8 Hz, J2 = 1.0
Hz), 7.87 (dt, 1H, J1 = 7.7 Hz, J2 = 1.7 Hz), 7.54 (ddd, 1H, J1 = 8.6 Hz, J2 =
6.9 Hz, J3 = 1.6 Hz), 7.46 (ddd, 1H, J1 = 7.6 Hz, J2 = 4.8 Hz, J3 = 1.2 Hz),
7.40ꢀ7.28 (m, 5H), 7.19ꢀ7.17 (m, 2H), 5.45 (s, 2H). 13C NMR (75
MHz, CDCl3, δ, ppm): 170.5, 162.6, 149.7, 148.6, 138.4, 137.3, 135.2,
132.8, 132.0, 129.1 (2C), 128.2, 127.1, 126.2, 126.0 (2C), 124.6, 123.2,
122.3, 121.8, 116,1, 57.2. MS (APCIþ) m/z: 356.0 [M þ H]þ. Anal.
Calcd for C22H17N3O2 (355.13) C 74.35, H 4.82, N 11.82; found: C
74.38, H 4.86, N 11.84.
4-Fluoro-N-(5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinolin-4-yl)benz-
amide (3f). The reaction was carried out with 1f (100 mg, 0.32 mmol)
for 3 h according to the general procedure to obtain 3f (99 mg,
0.31 mmol):
Yield 96%, yellow solid, mp 189ꢀ191 220ꢀ222 °C, Rf = 0.10
(CH2Cl2/AcOEt: 6/4). IR 1657, 1579, 1487, 1293, 1226, 1159, 849,
758, 694, 619 cmꢀ1. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.69 (s, 1H),
8.35 (d, 1H, J = 8.0 Hz), 7.95 (dd, 2H, J1 = 8.4 Hz, J2 = 5.5 Hz), 7.60
(t, 1H, J = 7.7 Hz), 7.32ꢀ7.26 (m, 2H), 6.96 (t, 2H, J = 8.5 Hz), 4.25 (t,
2H, J = 7.4 Hz), 3.28 (t, 2H, J = 7.8 Hz), 2.29 (p, 2H, J = 7.6 Hz). 13
C
NMR (100 MHz, CDCl3, δ, ppm): 173.3, 164.7, 164.6 (d, JCꢀF = 251.8
Hz), 151.8, 137.5, 131.7, 130.1 (d, 2C, JCꢀF = 9.1 Hz), 130.0, 126.7,
125.0, 123.2, 116.0, 115.5, 115.1 (d, 2C, JCꢀF = 21.8 Hz), 51.1, 31.7,
21.0. MS (APCIþ) m/z: 323.0 [M þ H]þ. Anal. Calcd for
C19H15FN2O2 (322.11) C 70.80, H 4.69, N 8.69; found: C 70.85, H
4.73, N 8.72.
N-(1-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)-2-nitrobenzamide
(3g). The reaction was carried out with 1a (100 mg, 0.35 mmol) for 16 h
according to the general procedure to obtain 3g (73 mg, 0.23 mmol):
Yield 64%, yellow solid, mp 148ꢀ150 °C °C, Rf = 0.20 (CH2Cl2/
AcOEt: 8/2). IR 3316, 1689, 1658, 1567, 1525, 1496, 1347, 1323, 1117,
856, 760, 700 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 9.25 (s, 1H),
9.10 (s, 1H), 8.39 (d, 1H, J = 8.0 Hz), 8.01 (d, 1H, J = 8.1 Hz), 7.73ꢀ7.65
(m, 3H), 7.55ꢀ7.46 (m, 2H), 7.38 (t, 1H, J = 7.4 Hz), 3.91 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ, ppm): 169.9, 164.3, 146.7, 138.9, 133.6,
133.2, 132.3 (2C), 130.8, 128.6, 126.8, 124.6, 124.1, 123.4, 122.1, 115.4,
41.3. MS (APCIþ) m/z: 324.0 [MþH]þ. Anal. Calcd for C17H13N3O4
(323.09) C 63.16, H 4.05, N 13.00; found: C 63.18, H 4.09, N 13.02.
N-(1-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)acetamide (3k). The
reaction was carried out with 1a (100 mg, 0.35 mmol) for 1 h according
to the general procedure to obtain 3k (71 mg, 0.33 mmol):
Yield 94%, beige solid, mp 219ꢀ221 °C, Rf = 0.20 (CH2Cl2/MeOH:
95/5). IR 3278, 1673, 1626, 1567, 1543, 1494, 1471, 1403, 1372, 1323,
1249, 1221, 1163, 1118, 1049, 911, 793, 743, 695 cmꢀ1. 1H NMR (300
MHz, CDCl3, δ, ppm): 9.15 (s, 1H), 8.49ꢀ8.46 (m, 2H), 7.68 (t, 1H, J =
7.8 Hz), 7.44 (d, 1H, J = 8.7 Hz), 7.38 (t, 1H, J = 7.5 Hz), 3.87 (s, 3H),
2.22 (s, 3H). 13C NMR (75 MHz, CDCl3, δ, ppm): 169.8, 168.8, 138.7,
132.5, 131.9, 126.8, 124.0, 123.1, 122.5, 115.3, 41.1, 24.3. MS (APCIþ)
m/z: 217.0 [M þ H]þ. Anal. Calcd for C12H12N2O2 (216.09) C 66.65,
H 5.59, N 12.96; found: C 66.67, H 5.60, N 12.96.
N-(2-(4-Methoxyphenyl)-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)
acetamide (3l). The reaction was carried out with 1d (100 mg, 0.26
mmol) for 7 h according to the general procedure to obtain 3l (46 mg,
0.14 mmol):
Yield 56%, brown solid, mp 231ꢀ233 °C, Rf = 0.20 (CH2Cl2/
MeOH: 9/1). IR 3234, 1685, 1589, 1569, 1494, 1471, 1431, 1365,
5001
dx.doi.org/10.1021/jo200680j |J. Org. Chem. 2011, 76, 4995–5005

The Journal of Organic Chemistry
ARTICLE
1290, 1246, 1172, 1113, 1030, 926, 872, 842, 823, 761, 723, 643 cmꢀ1. 1H
NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, 1H, J = 7.6 Hz), 7.82 (s, 1H),
7.64 (t, 1H J = 7.4 Hz), 7.46 (d, 1H J = 8.5 Hz), 7.38 (t, 1H, J = 7.1 Hz),
7.33 (d, 2H, J = 8.3 Hz), 6.99 (d, 2H, J = 8.3 Hz), 3.85 (s, 3H), 3.50 (s,
3H), 1.86 (s, 3H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.2, 170.1,
160.1, 153.0, 140.9, 132.2, 130.1 (2C), 126.7, 126.2, 125.5, 123.6, 118.7,
116.0, 113.8 (2C), 55.3, 37.5, 22.9. MS (APCIþ) m/z: 323.0 [M þ H]þ.
Anal. Calcd for C19H18N2O3 (322.13) C 70.79, H 5.63, N 8.69; found: C
70.83, H 5.67, N 8.72.
31.5, 28.9, 28.7, 26.5, 22.4, 13.9. MS (APCIþ) m/z: 337.0 [M þ H]þ.
Anal. Calcd for C17H24N2O3S (336.15) C 60.69, H 7.19, N 8.33; found:
C 60.71, H 7.22, N 8.35.
ꢀ
3-(1H-Indol-1-yl)-1-methylquinolin-4(1H)-one (4a). The reaction
was carried out with 1a (50 mg, 0.17 mmol) for 14 h according to the
general procedure to obtain 4a (47 mg, 0.17 mmol):
Yield 98%, yellow solid, mp 166ꢀ168 °C, Rf =0.52(CH2Cl2/AcOEt: 8/2).
IR 1585, 1555, 1509, 1453, 1364, 1305, 1268, 1238, 1213, 1122, 1066,
945, 837, 735, 699, 657 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm):
8.52 (dd, 1H, J1 = 8.4 Hz, J2 = 1.3 Hz), 7.77 (s, 1H), 7.77ꢀ7.70 (m, 1H),
7.63ꢀ7.60 (m, 1H), 7.46ꢀ7.41 (m, 2H), 7.23ꢀ7.18 (m, 2H),
7.10ꢀ7.07 (m, 2H), 6.60 (d, 1H, J = 3.0 Hz), 3.72 (s, 3H). 13C NMR
(75 MHz, CDCl3, δ, ppm): 173.2, 141.7, 139.8, 137.0, 132.4, 129.3,
128.5, 127.4, 127.3, 124.1, 121.8, 121.1, 120.7, 119.8, 115.5, 110.3, 102.7,
40.6. MS (APCIþ) m/z: 275.0 [M þ H]þ. Anal. Calcd for C18H14N2O
(274.11) C 78.81, H 5.14, N 10.21; found: C 78.83, H 5.19, N 10.22.
1-Heptyl-3-(3-methyl-1H-indol-1-yl)quinolin-4(1H)-one (4b). The
reaction was carried out with 1e (100 mg, 0.27 mmol) for 14 h according
to the general procedure to obtain 4b (98 mg, 0.26 mmol):
Yield 97%, beige solid, mp 108ꢀ110 °C, Rf = 0.80 (CH2Cl2/AcOEt:
9/1). IR 2927, 1591, 1555, 1494, 1455, 1396, 1230, 914, 765, 742, 705,
654 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.56 (dd, 1H, J1 = 8.1
Hz, J2 = 1.4 Hz), 7.82 (s, 1H), 7.70 (ddd, 1H, J1 = 8.5 Hz, J2 = 7.2 Hz, J3 =
1.4 Hz), 7.60ꢀ7.56 (m, 1H), 7.49 (d, 1H, J = 8.6 Hz), 7.41 (t, 1H, J = 7.5
Hz), 7.22ꢀ7.09 (m, 4H), 4.06 (t, 2H, J = 7.2 Hz), 2.36 (s, 3H),
1.88ꢀ1.83 (m, 2H), 1.36ꢀ1.31 (m, 8H), 0.91 (t, 3H, J = 6.6 Hz). 13C
NMR (100 MHz, CDCl3, δ, ppm): 173.1, 140.7, 138.7, 137.1, 132.1,
129.0, 127.6, 127.5, 126.8, 123.7, 121.7, 121.1, 119.1, 118.8, 115.4, 111.6,
109.9, 53.2, 31.5, 28.8, 28.7, 26.6, 22.4, 13.9, 9.5. MS (APCIþ) m/z:
373.0 [M þ H]þ. Anal. Calcd for C25H28N2O (372.22) C 80.61, H 7.58,
N 7.52; found: C 80.63, H 7.62, N 7.56.
1-Benzyl-3-(2-oxopyrrolidin-1-yl)quinolin-4(1H)-one (3m). The
reaction was carried out with 1c (100 mg, 0.28 mmol) for 1 h according
to the general procedure to obtain 3m (79 mg, 0.25 mmol):
Yield 89%, white solid, mp 259ꢀ261 °C, Rf = 0.25 (CH2Cl2/MeOH:
95/5). IR 1685, 1593, 1491, 1411, 1371, 1325, 1222, 766, 748, 702, 652,
1
622 cmꢀ1. H NMR (300 MHz, CDCl3, δ, ppm): 8.48 (dd, 1H, J1 =
8.3 Hz, J2 = 1.6 Hz), 8.10 (s, 1H), 7.54 (ddd, 1H, J1 = 8.8 Hz, J2 = 7.1 Hz,
J3 = 1.6 Hz), 7.37ꢀ7.30 (m, 5H), 7.19 (d, 2H, J = 8.1 Hz), 5.36 (s, 2H),
4.05 (t, 2H, J = 7.1 Hz), 2.55 (t, 2H, J = 8.1 Hz), 2.19 (m, 2H). 13C NMR
(75 MHz, CDCl3, δ, ppm): 175.6, 173.5, 142.5, 139.0, 134.8, 132.1,
129.2 (2C), 128.3, 127.6, 127.1, 126.2 (2C), 123.8, 119.9, 116.1, 56.9,
48.7, 31.1, 18.6. MS (APCIþ) m/z: 319 [M þ H]þ. Anal. Calcd for
C20H18N2O2 (318.14) C 75.45, H 5.70, N 8.80; found: C 75.47, H 5.72,
N 8.81.
1-Heptyl-3-(2-oxoazetidin-1-yl)quinolin-4(1H)-one (3n). The re-
action was carried out with 1e (100 mg, 0.27 mmol) for 1 h according to
the general procedure to obtain 3n (83 mg, 0.26 mmol):
Yield 97%, white solid, mp 95ꢀ97 °C, Rf = 0.10 (CH2Cl2/AcOEt: 9/1).
IR 2925, 2859, 1735, 1621, 1581, 1547, 1497, 1466, 1430, 1392, 1365,
1
1314, 1223, 1173, 1039, 899, 845, 803, 756, 705 cmꢀ1. H NMR (300
MHz, CDCl3, δ, ppm):8.50 (s, 1H), 8.42 (dd, 1H, J1 = 8.2 Hz, J2 =1.5 Hz),
7.61 (ddd, 1H, J1 =8.6Hz, J2 =7.0Hz, J3 =1.6Hz), 7.40(d, 1H, J=8.6Hz),
7.31 (ddd, 1H, J1 = 7.9 Hz, J2 = 7.1 Hz,J3 = 0.8 Hz), 4.15 (t, 2H, J = 4.4 Hz),
4.09 (t, 2H, J = 7.5 Hz), 3.10 (t, 2H, J = 4.4 Hz), 1.87ꢀ1.77 (m, 2H),
1.34ꢀ1.25 (m, 8H), 0.84 (t, 3H, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3,
δ, ppm): 171.0, 166.1, 137.8, 134.5, 131.7, 126.8 (2C), 123.1, 120.6, 115.3,
53.5, 42.4, 38.4, 31.5, 28.9, 28.7, 26.5, 22.4, 13.9. MS (APCIþ) m/z: 313.0
[Mþ H]þ. Anal. CalcdforC19H24N2O2 (312.18) C 73.05, H 7.74, N 8.97;
found: C 73.08, H 7.77, N 8.99.
4-Methyl-N-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)benzene-
sulfonamide (3o). The reaction was carried out with 1a (100 mg, 0.35
mmol) for 48 h according to the general procedure to obtain 3o (61 mg,
0.18 mmol):
1-Heptyl-3-(5-methyl-1H-indol-1-yl)quinolin-4(1H)-one (4c). The
reaction was carried out with 1e (100 mg, 0.27 mmol) for 14 h according
to the general procedure to obtain 4c (96 mg, 0.26 mmol):
Yield 95%, white solid, mp 132ꢀ134 °C, Rf = 0.78 (CH2Cl2/AcOEt:
8/2). IR 2923, 1592, 1487, 1383, 1222, 907, 843, 756, 722, 704, 654, 592,
579, 567, 543 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.56 (d, 1H,
J = 8.0 Hz), 7.83 (s, 1H), 7.71 (t, 1H, J = 7.4 Hz), 7.50 (d, 1H, J = 8.7 Hz),
7.43ꢀ7.39 (m, 2H), 7.29 (d, 1H, J = 3.2 Hz), 7.13 (d, 1H, J = 8.3 Hz),
6.96 (d, 1H, J = 8.5 Hz), 6.56 (d, 1H, J = 3.1 Hz), 4.09 (t, 2H, J = 7.2 Hz),
2.44 (s, 3H), 1.89ꢀ1.82 (m, 2H), 1.35ꢀ1.30 (m, 8H), 0.90 (t, 3H, J =
6.6 Hz). 13C NMR (75 MHz, CDCl3, δ, ppm): 173.0, 140.7, 138.8,
135.3, 132.2, 129.4, 129.0, 128.8, 127.7, 127.6, 123.8, 123.4, 121.2, 120.4,
115.4, 109.7, 102.2, 53.4, 31.5, 28.8, 28.7, 26.7, 22.4, 21.3, 13.9. MS
(APCIþ) m/z: 373.0 [M þ H]þ. Anal. Calcd for C25H28N2O (372.22)
C 80.61, H 7.58, N 7.52; found: C 80.63, H 7.65, N 7.56.
4-(5-Methoxy-1H-indol-1-yl)-2,3-dihydropyrrolo[1,2-a]quinolin-5(1H)-
one (4d). The reaction was carried out with 1g (100 mg, 0.38 mmol) for 48
h according to the general procedure to obtain 4d (95 mg, 0.29 mmol):
Yield 76%, white solid, mp 128ꢀ130 °C, Rf = 0.35 (CH2Cl2/AcOEt:
8/2). IR 1620, 1588, 1550, 1503, 1470, 1446, 1390, 1342, 1288, 1263,
1232, 1161, 1070, 1026, 821, 757, 706, 617 cmꢀ1. 1H NMR (300 MHz,
CDCl3, δ, ppm): 8.47 (dd, 1H, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.68 (ddd, 1H,
J1 = 8.5 Hz, J2 = 7.2 Hz, J3 = 1.5 Hz), 7.42ꢀ7.35 (m, 2H), 7.12ꢀ7.10 (m,
2H), 6.90 (d, 1H, J = 8.8 Hz), 6.76 (dd, 1H, J1= 8.8 Hz, J2 = 2.4 Hz), 6.57
(d, 1H, J = 3.1 Hz), 4.35ꢀ4.27 (m, 2H), 3.82 (s, 3H), 2.92 (t, 2H, J =
7.7 Hz), 2.25 (p, 2H, J = 7.7 Hz). 13C NMR (75 MHz, CDCl3, δ, ppm):
173.9, 154.2, 154.1, 138.1, 132.1, 131.8, 129.7, 128.7, 127.3, 126.6, 123.8,
117.1, 115.7, 111.8, 110.8, 102.6, 102.4, 55.8, 51.1, 30.1, 20.8. MS
(APCIþ) m/z: 331.0 [M þ H]þ. Anal. Calcd for C21H18N2O2 (330.14)
C 76.34, H 5.49, N 8.48; found: C 76.36, H 5.53, N 8.51.
Yield 53%, white solid, mp 260ꢀ262 °C, Rf =0.17(CH2Cl2/AcOEt: 8/2).
IR 1715, 1627, 1580, 1447, 1389, 1306, 1196, 1155, 1116, 1091, 993,
1
816, 768, 718, 673, 617, 581, 568, 552. cmꢀ1. H NMR (300 MHz,
CDCl3, δ, ppm): 8.33 (d, 1H, J = 8.2 Hz), 8.15 (s, 1H), 7.71ꢀ7.66 (m,
3H) 7.46ꢀ7.35 (m, 3H), 7.17 (d, 2H, J = 7.8 Hz), 3.89 (s, 3H) 2.31 (s,
3H). 13C NMR (75 MHz, DMSO-d6, δ, ppm): 170.9, 142.5, 140.9,
139.2, 137.6, 131.9, 129.0 (2C), 126.7 (2C), 125.5, 125.2, 123.4, 117.7,
116.7, 40.3, 20.8. MS (APCIþ) m/z: 329.0 [M þ H]þ. Anal. Calcd for
C17H16N2O3S (328.09) C 62.18, H 4.91, N 8.53; found: C 62.19, H
4.94, N 8.54.
N-(1-Heptyl-4-oxo-1,4-dihydroquinolin-3-yl)methanesulfonamide (3p).
The reaction was carried out with 1e (100 mg, 0.27 mmol) for 60 h
according to the general procedure to obtain 3p (60 mg, 0.18 mmol,
65%) as a brown solid:
Yield 65%, brown solid, mp 143ꢀ145 °C, Rf = 0.15 (CH2Cl2/AcOEt:
8/2). IR 2920, 2851, 1621, 1580, 1545, 1498, 1449, 1406, 1323, 1281,
1225, 1151, 996, 799, 758, 706, 650, 615 cmꢀ1. 1H NMR (300 MHz,
CDCl3, δ, ppm): 8.48 (d, 1H, J = 8.1 Hz), 8.05 (s, 1H), 7.71 (t, 1H, J =
7.8 Hz), 7.50 (d, 1H, J = 8.7 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.29 (bs, 1H),
4.19 (t, 2H, J = 7.4 Hz), 2.92 (s, 3H), 1.89ꢀ1.85 (m, 2H), 1.36ꢀ1.23
(m, 8H), 0.85 (t, 3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3, δ, ppm):
172.0, 138.6, 138.2, 132.4, 127.1, 125.7, 123.9, 119.1, 115.6, 53.8, 39.0,
4-(5-Chloro-1H-indol-1-yl)-2,3-dihydropyrrolo[1,2-a]quinolin-5(1H)-
one (4e). The reaction was carried out with 1f (100 mg, 0.32 mmol) for 36
h according to the general procedure to obtain 4e (44 mg, 0.13 mmol):
5002
dx.doi.org/10.1021/jo200680j |J. Org. Chem. 2011, 76, 4995–5005

The Journal of Organic Chemistry
ARTICLE
Yield 41%, rose solid, mp 210ꢀ212 °C, Rf = 0.50 (CH2Cl2/AcOEt:
8/2). IR 1589, 1552, 1502, 1450, 1385, 1325, 1286, 1215, 1021, 907,
870, 797, 753, 721, 705 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm):
8.47 (dd, 1H, J1 = 8.1 Hz, J2 = 1.4 Hz), 7.71 (ddd, 1H, J1 = 8.5 Hz, J2 = 7.3
Hz, J3 = 1.5 Hz), 7.59 (d, 1H, J = 2.0 Hz), 7.44ꢀ7.37 (m, 2H), 7.15 (d,
1H, J = 3.2 Hz), 7.04 (dd, 1H, J1 = 8.7 Hz, J2 = 2.0 Hz), 6.91 (d, 1H, J =
8.7 Hz), 6.58 (d, 1H, J = 3.1 Hz), 4.38ꢀ4.32 (m, 2H), 2.95ꢀ2.88 (m,
2H), 2.34ꢀ2.24 (m, 2H). 13C NMR (75 MHz, CDCl3, δ, ppm): 173.8,
154.2, 138.1, 135.0, 132.3, 130.5, 129.4, 127.3, 126.6, 125.3, 124.0, 122.0,
120.1, 116.5, 115.7, 111.2, 102.4, 51.1, 30.1, 20.8. MS (APCIþ) m/z:
335.0 ([M þ H]þ, 35Cl), 337.0 ([M þ H]þ, 37Cl). Anal. Calcd for
C20H15ClN2O (334.09) C 71.75, H 4.52, N 8.37; found: C 71.77, H
4.63, N 8.40.
1-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)quinolin-4(1H)-one (4f).
The reaction was carried out with 1a (50 mg, 0.17 mmol) for 96 h
according to the general procedure to obtain 4f (42 mg, 0.15 mmol):
Yield 87%, ochre solid, mp 179ꢀ181 °C, Rf = 0.40 (CH2Cl2/MeOH:
95/5). IR 1587, 1552, 1511, 1422, 1331, 1214, 752, 662 cmꢀ1. 1H NMR
(300 MHz, CDCl3, δ, ppm): 8.54 (d, 1H, J = 8.1 Hz), 8.31 (s, 1H), 8.26
(d, 1H, J = 3.2 Hz), 7.94 (d, 1H, J = 7.1 Hz), 7.76 (d, 1H, J = 3.6 Hz), 7.71
(dt, 1H, J1 = 8.4 Hz, J2 = 1.2 Hz), 7.45ꢀ7.40 (m, 2H), 7.08 (dd, 1H, J1 =
7.5 Hz, J2 = 4.8 Hz), 6.60 (d, 1H, J = 3.4 Hz), 3.89 (s, 3H). 13C NMR (75
MHz, CDCl3, δ, ppm): 173.0, 147.8, 142.7, 141.8, 139.6, 132.3, 130.3,
128.8, 127.4, 127.2, 124.0, 120.9, 119.3, 116.4, 115.4, 100.4, 41.1. MS
(APCIþ) m/z: 276.0 [M þ H]þ. Anal. Calcd for C17H13N3O (275.11)
C 74.17, H 4.76, N 15.26; found: C 74.20, H 4.79, N 15.28.
302.0 [M þ H]þ. Anal. Calcd for C19H15N3O (301.12) C, 75.73; H
5.02, N 13.94; found: C, 75.76; H 5.09, N 13.96.
4-Methoxy-N-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)benzamide
(6a). The reaction was carried out with 5a (50 mg, 0.21 mmol) for 2 h
according to the general procedure to obtain 6a (63 mg, 0.21 mmol):
Yield: 98%; mp 181ꢀ183 °C; Rf = 0.74 (CH2Cl2/EtOAc: 8:2); IR
(neat): 3375, 1669, 1638, 1619, 1598, 1576, 1527, 1494, 1465, 1421,
1377, 1327, 1296, 1255, 1217, 1177, 1115, 1023, 965, 947, 907, 858, 838,
800, 777, 752, 739, 716, 692, 621, 598, 559 cmꢀ1. 1H NMR (300 MHz,
CDCl3): δ 9.24 (s, 1H), 8.78 (s, 1H), 7.85 (d, 2H, J = 9.0 Hz), 7.55 (dd,
1H, J1 = 7.8, J2 = 1.5 Hz), 7.40 (td, 1H, J1 = 8.7, J2 = 1.5 Hz), 7.27 (d, 1H,
J = 8.4 Hz), 7.19 (td, 1H, J1 = 8.1, J2 = 1.2 Hz), 6.69 (d, 2H, J = 9.0 Hz),
3.79 (s, 3H), 3.74 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.3 (CO),
162.7, 158.2 (CO), 135.5, 129.1 (2CH), 128.9, 128.8, 127.9, 126.5,
123.1, 121.2, 120.1, 114.5 (2CH), 114.0, 55.5 (OCH3), 30.3 (CH3);
m/z MS (ESþ) 331.0 (M þ Naþ); Anal. Calcd for C18H16N2O3
(308.12): C 70.12, H 5.23 N, 9.09; found: C 70.14, H 5.26 N, 9.10.
Ethyl 2-(2-Oxo-3-(thiophene-2-carboxamido)quinolin-1(2H)-yl)
acetate (6b). The reaction was carried out with 5b (100 mg, 0.32
mmol) for 12 h according to the general procedure to obtain 6b (85 mg,
0.24 mmol):
Yield 74%, white solid, mp 160ꢀ162 °C, Rf = 0.76 (CH2Cl2). IR 1753,
1633, 1599, 1526, 1492, 1416, 1372, 1200, 1023, 727, 640 cmꢀ1. 1H NMR
(300 MHz, CDCl3, δ, ppm): 9.11 (s, 1H), 8.84 (s, 1H), 7.67 (d, 1H, J = 3.7
Hz), 7.63 (dd, 1H, J1 = 7.8 Hz, J2 = 1.0 Hz), 7.56 (d, 1H, J= 4.9 Hz), 7.45 (t,
1H, J = 7.2 Hz), 7.27 (t, 1H, J = 7.5 Hz), 7.14ꢀ7.11 (m, 2H), 5.15 (s, 2H),
4.25 (q, 2H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz,
CDCl3, δ, ppm): 167.5, 160.2, 157.9, 138.8, 134.8, 131.4, 129.0, 128.9,
128.7, 127.9, 127.1, 123.4, 121.3, 121.0, 113.2, 61.9, 44.6, 14.0. MS (APCIþ)
m/z: 357.0 [M þ H]þ. Anal. Calcd for C18H16N2O4S (356.08) C 60.66, H
4.53, N 7.86; found: C 60.68, H 4.59, N 7.90.
1-Benzyl-3-(1H-indazol-1-yl)quinolin-4(1H)-one (4g). The reac-
tion was carried out with 1c (100 mg, 0.28 mmol) for 14 h according
to the general procedure to obtain 4g (84 mg, 0.24 mmol):
Yield86%,brownsolid,mp145ꢀ147 °C, Rf =0.20(CH2Cl2/AcOEt: 8/2).
IR 2926, 1615, 1590, 1489, 1464, 1423, 1378, 1300, 1199, 1025, 909,
1
853, 762, 728, 695, 654, 623 cmꢀ1. H NMR (300 MHz, CDCl3, δ,
3-(1H-Indol-1-yl)-1-methylquinolin-2(1H)-one (6c). The reaction
was carried out with 5a (100 mg, 0.42 mmol) for 12 h according to the
general procedure to obtain 6c (63 mg, 0.23 mmol):
ppm): 8.59 (d, 1H, J = 8.0 Hz), 8.17 (bs, 2H), 7.74 (d, 1H, J = 8.1 Hz),
7.60ꢀ7.55 (m, 1H), 7.47ꢀ7.29 (m, 7H), 7.20ꢀ7.17 (m, 3H), 5.36
(s, 2H). 13C NMR (75 MHz, CDCl3, δ, ppm): 171.9, 142.1, 139.1,
135.4, 134.5 (2C), 132.4, 129.2 (2C), 128.3, 127.5, 126.6, 126.1 (2C),
124.2, 122.8, 121.1, 120.7, 116.3, 112.0, 56.8, one C mising. MS
(APCIþ) m/z: 352.0 [M þ H]þ. Anal. Calcd for C23H17N3O
(351.14) C 78.61, H 4.88, N 11.96; found: C 78.65, H 4.90, N 11.98.
1-Benzyl-3-(1H-pyrrol-1-yl)quinolin-4(1H)-one (4i). The reaction
was carried out with 1c (100 mg, 0.28 mmol) for 14 h according to the
general procedure to obtain 4i (69 mg, 0.23 mmol):
Yield 83%, violet solid, mp 180ꢀ182 °C, Rf = 0.40 (CH2Cl2/AcOEt:
9/1). IR 1589, 1486, 1355, 1260, 1107, 1066, 835, 756, 724, 700, 658,
635 cmꢀ1. 1H NMR (300 MHz, CDCl3, δ, ppm): 8.55 (d, 1H, J = 8.2
Hz), 7.85 (s, 1H), 7.57 (t, 1H, J = 8.6 Hz), 7.39ꢀ7.32 (m, 5H), 7.17 (d,
2H, J = 7.9 Hz), 7.07 (t, 2H, J = 2.1 Hz), 6.30 (t, 2H, J = 2.1 Hz), 5.37 (s,
2H). 13C NMR (100 MHz, CDCl3, δ, ppm): 172.4, 138.9, 138.0, 134.7,
132.2, 129.2 (2C), 128.4, 127.4 (2C), 126.1 (2C), 123.8, 123.7, 121.5,
116.0, 109.0 (2C), 56.5, one C mising. MS (APCIþ) m/z: 301.0 [M þ
H]þ. Anal. Calcd for C20H16N2O (300.13) C 79.98, H 5.37, N 9.33;
found: C 79.99, H 5.40, N 9.36.
Yield 54%, orange solid, mp 193ꢀ195 °C, Rf = 0.75 (CH2Cl2). IR
1641, 1594, 1449, 1322, 1232, 946, 731, 705, 649 cmꢀ1. 1H NMR (300
MHz, CDCl3, δ, ppm): 7.77 (s, 1H), 7.56 (d, 1H, J = 7.6 Hz), 7.52ꢀ7.43
(m, 3H), 7.33ꢀ7.29 (m, 2H), 7.19 (t, 1H, J = 7.5 Hz), 7.13ꢀ7.03 (m,
2H), 6.58 (d, 1H, J = 3.3 Hz), 3.72 (s, 3H). 13C NMR (75 MHz, CDCl3,
δ, ppm): 159.1, 138.5, 136.3, 131.9, 130.4, 129.3, 129.1, 128.9, 128.6,
122.7, 122.1, 121.0, 120.4, 119.6, 114.1, 110.6, 103.5, 30.2. MS (APCIþ)
m/z: 275.0 [M þ H]þ. Anal. Calcd for C18H14N2O (274.11) C 78.81, H
5.14, N 10.21; found: C 78.86, H 5.16, N 10.26.
N-(6-Bromo-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4-fluoro-
benzamide (6d). The reaction was carried out with 5c (50 mg, 0.16
mmol) for 3 h according to the general procedure to obtain 6d (38 mg,
0.10 mmol):
Yield 65%, white solid, mp 228ꢀ230 °C, Rf = 0.57 (CH2Cl2/c-
hexane: 8/2). IR 3366, 1672, 1638, 1614, 1593, 1532, 1504, 1487, 1426,
1
1365, 1204, 1165, 1098, 920, 874, 855, 809, 754, 656, 617 cmꢀ1. H
NMR (300 MHz, CDCl3, δ, ppm): 9.25 (s, 1H), 8.69 (s, 1H), 7.91ꢀ7.87
(m, 2H), 7.68 (d, 1H, J = 2.1 Hz), 7.50 (dd, 1H, J1 = 8.9 Hz, J2 = 2.1 Hz),
7.19ꢀ7.08 (m, 3H), 3.73 (s, 3H). 13C NMR (75 MHz, CDCl3, δ, ppm):
165.2(d, 1C, JCꢀF = 253.4Hz), 164.7, 157.8, 134.5, 131.4, 130.6, 130.1(d,
1C, JCꢀF = 2.7 Hz), 129.7, 129.6, 128.5, 122.7, 119.0, 116.2, 116.1, 115.8,
115.6, 30.5. MS (APCIþ) m/z: 375.0 ([M þ H]þ, 79Br), 377.0 ([M þ
H]þ, 81Br). Anal. Calcd for C17H12BrFN2O2 (374.01) C 54.42, H 3.22, N
7.47; found: C 54.43, H 3.26, N 7.47.
N-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-methoxy-
benzamide (6e). The reaction was carried out with 5e (100 mg,
0.37 mmol) for 3 h according to the general procedure to obtain 6e
(86 mg, 0.25 mmol):
1-Benzyl-3-(1H-imidazol-1-yl)quinolin-4(1H)-one (4j). The reac-
tion was carried out with 1c (100 mg, 0.28 mmol) for 84 h according to
the general procedure to obtain 4j (57 mg, 0.19 mmol):
Yield 68%, light yellow solid, mp 215ꢀ217 °C, Rf = 0.43 (CH2Cl2/
MeOH: 9/1). IR 3059, 1634, 1575, 1556, 1510, 1489, 1467, 1451, 1381,
1310, 1260, 1233, 1165, 1148, 1110, 1064, 1032, 975, 940, 905, 841, 813,
1
754, 728, 692, 657, 617, 608 cmꢀ1. H NMR (300 MHz, CDCl3, δ,
ppm): 8.51 (dd, 1H, J1 = 8.1 Hz, J2 = 1.5 Hz), 7.96 (s, 1H), 7.88 (s, 1H),
7.61 (ddd, 1H, J1 = 8.6 Hz, J2 = 7.0 Hz, J3 = 1.6 Hz), 7.43ꢀ7.26 (m, 6H),
7.19ꢀ7.13 (m, 3H), 5.42 (s, 2H). 13C NMR (75 MHz, CDCl3, δ, ppm):
171.9, 139.2, 138.3, 137.3, 134.3, 132.7, 129.3 (2C), 128.9, 128.6, 127.3
(2C), 126.2 (2C), 124.4, 120.2, 119.9, 116.2, 56.6. MS (APCIþ) m/z:
Yield 68%, white solid, mp 163ꢀ165 °C, Rf = 0.50 (Et2O). IR 1644,
1
1598, 1500, 1349, 1221, 1173, 1027, 756, 613 cmꢀ1. H NMR (300
5003
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The Journal of Organic Chemistry
ARTICLE
MHz, CDCl3, δ, ppm): 9.09 (s, 1H), 8.59 (s, 1H), 7.85 (d, 2H, J = 8.6
Hz), 7.12 (s, 1H), 6.94 (d, 2H, J = 8.6 Hz), 3.83 (s, 3H), 3.57 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ, ppm): 165.1, 162.7, 156.5, 129.8 (2C), 129.0
(2C), 125.9, 124.3, 113.9 (2C), 99.2, 55.4, 37.7. MS (APCIþ) m/z:
337.0 ([M þ H]þ, 79Br), 339.0 ([M þ H]þ, 81Br). Anal. Calcd for
C14H13BrN2O3 (336.01) C 49.87, H 3.89, N 8.31; found: C 49.89, H
3.93, N 8.35.
5-Bromo-1-methyl-3-(2-oxoazetidin-1-yl)pyridin-2(1H)-one (6f).
The reaction was carried out with 5e (100 mg, 0.37 mmol) for 12 h
according to the general procedure to obtain 6f (55 mg, 0.21 mmol):
Yield 57%, white solid, mp 241ꢀ243 °C, Rf = 0.30 (Et2O). IR 3079,
1729, 1641, 1584, 1391, 1320, 1081, 882, 726, 612 cmꢀ1. 1H NMR (300
MHz, CDCl3, δ, ppm): 8.03 (d, 1H, J = 2.5 Hz), 7.13 (d, 1H, J = 2.5 Hz),
4.12 (t, 2H, J = 4.6 Hz), 3.48 (s, 3H), 3.08 (t, 2H, J = 4.6 Hz). 13C NMR
(75 MHz, CDCl3, δ, ppm): 166.6, 156.1, 131.9, 128.7, 127.4, 97.8, 43.0,
38.5, 37.6. MS (ESIþ) m/z: 279.0 ([M þ Na]þ, 79Br), 281.0
([M þ Na]þ, 81Br). Anal. Calcd for C9H9BrN2O2 (255.98) C 42.05
H 3.53; N 10.90; found: C 42.09 H 3.59; N 10.92.
Morvan for her help in the NMR experiments and A. Solgadi for
performing mass spectra analysis (SAMM platform, Ch^atenay-
Malabry).
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6-Bromo-1-methyl-3-(1H-pyrrol-1-yl)quinolin-2(1H)-one (6g). The
reaction was carried out with 5c (50 mg, 0.16 mmol) for 18 h according
to the general procedure to obtain 6g (20 mg, 0.07 mmol):
Yield 42%, white solid, mp 168ꢀ170 °C, Rf = 0.60 (CH2Cl2). IR
1650, 1587, 1476, 1422, 1308, 1254, 1099, 902, 816, 723, 666, 620 cmꢀ1
.
1H NMR (300 MHz, CDCl3, δ, ppm): 7.73 (d, 1H, J = 1.9 Hz), 7.65 (dd,
1H, J1 = 9.0 Hz, J2 = 1.9 Hz), 7.54 (s, 1H), 7.30ꢀ7.27 (m, 3H),
6.37ꢀ7.36 (m, 2H), 3.81 (s, 3H). 13C NMR (75 MHz, CDCl3, δ, ppm):
158.0, 136.7, 132.5, 131.5, 130.5, 125.9, 121.4, 121.3 (2C), 115.7, 115.5,
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3.66, N 9.24; found: C 55.50, H 3.69, N 9.29.
4-Methoxy-N-(2-oxo-2H-chromen-3-yl)benzamide (6h). The re-
action was carried out with 5d (100 mg, 0.44 mmol) for 1.5 h according
to the general procedure to obtain 6h (54 mg, 0.18 mmol, 41%) as a
white solid:
Yield 41%, white solid, mp 177ꢀ179 °C, Rf = 0.48 (CH2Cl2). IR
3401, 1712, 1667, 1604, 1578, 1507, 1446, 1359, 1296, 1246, 1190, 1112,
1063, 925, 910, 859, 842, 754, 691, 643, 606, 568 cmꢀ1. 1H NMR (300
MHz, CDCl3, δ, ppm): 8.77 (s, 1H), 8.69 (bs,1H), 7.82 (d, 2H, J = 8.8
Hz), 7.47 (dd, 1H, J1 = 7.7 Hz, J2 = 1.3 Hz), 7.38 (td, 1H, J1 = 8.4 Hz,
J2 = 1.5 Hz), 7.30 ꢀ7.18 (m, 2H), 6.92 (d, 2H, J = 8.8 Hz), 3.81 (s, 3H).
13C NMR (75 MHz, CDCl3, δ, ppm): 165.6, 163.1, 159.1, 149.8, 129.6,
129.2 (2C), 127.9, 125.7, 125.2, 124.3, 123.0, 120.0, 116.4, 114.2 (2C),
55.5. MS (ESIþ) m/z: 318.0 [M þ Na]þ. Anal. Calcd for C17H13NO4
(295.08) C 69.15, H 4.44, N 4.74; found: C 69.19, H 4.49, N 4.79.
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’ ASSOCIATED CONTENT
(7) (a) Messaoudi, S.; Trꢀeguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.;
De Losada, J. R.; Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.;
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O.; Trꢀeguier, B.; De Losada, J. R.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.;
Thoret, S.; Dubois, J.; Brion, J.-D.; Alami ChemMedChem 2011, 6, 488–497.
(8) (a) Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Anticancer
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S
Supporting Information. Copies of NMR spectra for all
b
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*samir.messaoudi@u-psud.fr, mouad.alami@u-psud.fr
(9) Audisio, D.; Messaoudi, S.; Brion, J.-B.; Alami, M. Eur. J. Org.
Chem. 2010, 1046–1051.
’ ACKNOWLEDGMENT
The Centre National de Recherche Scientifique [CNRS] is
gratefully acknowledged for financial support of this research. We
thank the European Union [EU] within the EST network
BIOMEDCHEM [MEST-CT-2005-020580] for a Ph.D. grant
(to Davide Audisio) and for financial support. Region Ile-de-
France is also acknowledged for support. Thanks also to E.
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ARTICLE
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