Microwave-assisted synthesis of polysubstituted 4-quinolones from deprotonated α-aminonitriles

Article abstract of DOI:10.1002/ejoc.201000858

The α-alkylation of deprotonated N-aryl-α-aminonitriles with α-bromoesters furnishes intermediates that can be cyclized to 4-quinolones upon microwave irradiation. Alternatively, base-induced dehydrocyanation of the alkylation products furnishes enaminoes

Full text of DOI:10.1002/ejoc.201000858

FULL PAPER
DOI: 10.1002/ejoc.201000858
Microwave-Assisted Synthesis of Polysubstituted 4-Quinolones from
Deprotonated α-Aminonitriles
Alexandra Romek[a] and Till Opatz*[b]
Keywords: Nitrogen heterocycles / Cyclization / Alkylation / Microwave chemistry
The α-alkylation of deprotonated N-aryl-α-aminonitriles with
α-bromoesters furnishes intermediates that can be cyclized
to 4-quinolones upon microwave irradiation. Alternatively,
base-induced dehydrocyanation of the alkylation products
furnishes enaminoesters, which can, for example, be con-
verted into quinoline-3-carboxylates.
resulting keteneiminate salts can serve as stabilized α-
aminocarbanion equivalents in the preparation of pyrroli-
dines, pyrroles, indoles, diamines, amino alcohols, or imid-
azoles.[8,9] Their alkylation with α-haloesters yields interme-
diates that slowly release HCN with formation of enamino
esters.[10] In the case of aniline-derived aminonitriles, these
compounds are susceptible to the Conrad–Limpach cycliza-
tion, which would permit the three-step synthesis of poly-
substituted 2-aryl-4-quinolones from an aniline, an aro-
matic aldehyde, and an α-haloester (Scheme 1).
Introduction
Their antibacterial properties make 4-quinolones an
interesting compound class for medicinal chemistry.[1] For
instance, the blockbuster antibiotics ciprofloxacin[2] and le-
vofloxacin[3] are based on a 4-quinolone scaffold. Moreover,
cytotoxic activities have been found for simple members of
the 2-aryl-substituted series. These could be attributed to
the interaction with the colchicine binding site on tubulin,
which results in the blocking of mitosis in a broad spectrum
of human cancer cell lines both in vitro and in vivo.[4] Nu-
merous methods have been developed for the preparation
of 4-quinolones, including the N-acylation of 2-aminoace-
tophenone and subsequent intramolecular condensation ac-
cording to Camps, the reaction of anthranilates with ketals,
or processes involving Cu- or Pd-catalyzed C–N bond for-
mation.[1a,4b,5] A classical and widely employed approach
is the Conrad–Limpach synthesis from anilines and β-keto
esters,[6] which is closely related to the Combes synthesis
of quinolines from anilines and β-diketones.[7] Herein, we
describe a modular approach relying on the same ring clo-
sure, which does not require the preformation of the C2–
C4 fragment and which uses only readily available classes
of starting materials.
Results and Discussion
Scheme 1. Modular synthesis of 4-quinolones by alkylation of de-
protonated aminonitriles.
Under certain conditions, Strecker products derived from
aromatic, heteroaromatic, or α,β-unsaturated aldehydes and
primary amines or ammonia can be deprotonated quantita-
tively without inducing the retro-Strecker reaction.[8] The
The concentrations of base and aminonitrile 3 were of
great importance for the suppression of the formation of
byproducts. The best results were seen with concentrations
of 40–120 m aminonitrile and 85–250 m KHMDS in dry
THF at –78 °C by using a short deprotonation period while
either increasing the concentrations of the reactants or ex-
tension of the deprotonation time led to a significant de-
crease in the reaction yield. Under these conditions, several
α,N-diaryl-α-aminonitriles and α-bromoesters were tested
View this journal online at
[a] Department of Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
[b] Institute for Organic Chemistry, University of Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
Fax: +49-6131-39-22338
E-mail: opatz@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000858.
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 5841–5849
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5841

A. Romek, T. Opatz
FULL PAPER
in C-alkylation reactions, and the results are shown in Table 2. Cyclization of compounds 4 into 4-quinolones.
Table 1. In all cases, moderate to good alkylation yields
were observed. As experienced with similar reactions by
using different electrophiles, electron-donating substituents
in the aminonitrile and steric hindrance in the α-bromoester
led to diminished yields. The introduction of a substituent
R3 ϶ H resulted in the formation of inconsequential dia-
stereomeric mixtures; in the case of 2 phenyl-substituted
aminonitrile 4j, separation of both diastereomers could be
achieved by flash chromatography.
Table 1. Alkylation of compounds 3 with α-haloesters.
Entry Aminonitrile R1
R2
R3
t
[h]
Product,
% Yield
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
H
H
H
H
1.5
4
2
4
0.5
1
4a, 87
4b, 70
4c, 67[a]
4d, 55
4e, 83[b]
4f, 33
4g, 61
4h,
4-CH3
4-OCH3
3-OCH3
3-Cl
H
H
H
4-OCH3
2-Cl
3g
1
8
3a
H
H
CH3
2
54[b,c]
9
10
3a
3a
H
H
H
H
C2H5
C6H5
1
4
4i, 63[c]
4j, 59[c]
[a] Contained trace amounts of starting material 3c. [b] Contained
trace amounts of impurities due to decomposition during flash
chromatography. [c] Mixture of diastereomers.
The thermal dehydrocyanation of alkylation products 4
furnishes enamino esters, qualified for the Conrad–Lim-
pach reaction although higher yields of the latter products
can be obtained under basic conditions (vide infra). How-
ever, heating of compounds 4 to 180–250 °C in inert sol-
vents such as diphenyl ether or decalin directly gives quino-
lones 6 in high yields.[11] A drastic increase in the reaction
rates was observed when switching from classical heating
(oil bath) to microwave irradiation, where complete conver-
sion could be achieved in 10–30 min instead of up to 12 h.
The results of a study involving all prepared intermediates
4 are summarized in Table 2.
While complete regioselectivity in favor of the 7-substi-
tuted product was observed for meta-methoxy-substituted
compound 4d, the corresponding chlorine derivative 4e gave
a 7:1 mixture of the 7- and 5-substituted quinolone. Due to
their low solubility in common organic solvents, 4-quino-
lone 6e and its 5-Cl isomer could not be separated by
chromatography. In contrast to the workup protocol by
Kuo et al.,[4a] purification of the products by flash
[a] In addition, 14% of 5-isomer 6k was obtained.
chromatography or recrystallization was not necessary, as high purity. For the preparation of enamino esters 5, micro-
the product precipitated from diphenyl ether during the re- wave heating of intermediates 4 to 100 °C in the presence
action. Precipitation was completed by addition of n-hex- of DBU turned out to be the method of choice. Well-known
ane, and washing with the same solvent gave products of β-anilinocinnamate 5a[5a,12] was thus obtained from 4a in
5842
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5841–5849

Polysubstituted 4-Quinolones from Deprotonated α-Aminonitriles
77% yield within 15 min as a 3:1 mixture of Z/E isomers.
Formylation of the material according to a procedure by
Anzini et al. gave ethyl 2-phenylquinoline-3-carboxylate (7)
in 81% yield (Scheme 2).[13]
Experimental Section
General Experimental Methods: All reactions were carried out in
dried glassware and under an argon atmosphere. THF was dried
by distillation from Na/benzophenone. Solvents used for flash
chromatography were distilled before use. Aminonitriles 3 were pre-
pared according to known procedures.[15–20] Other solvents and rea-
gents were purchased from commercial suppliers and were used
without further purification. TLC experiments were performed on
glass plates coated with silica gel (60 F254, Merck). Spots were visu-
alized with UV-light at 254 nm and developed with phosphomolyb-
dic acid, which was prepared by dissolving phosphomolybdic acid
(25 g), Ce(SO4)2·4H2O (10 g), and H2SO4 (60 mL) in water
(940 mL).[21] Flash chromatography was carried out on silica gel
1
(32–63 µm, Acros). H and 13C NMR spectra were recorded with
a Bruker AV-400 or DRX 500 spectrometer and signals were re-
ferred to the residual solvent signal (CDCl3: δH = 7.26 ppm, δC
=
77.16 ppm; CD3OD: δH = 3.31 ppm, δC = 49.00 pm; [D6]DMSO:
δH = 2.50 ppm, δC = 39.52 ppm).[22] Low- and high-resolution mass
spectra in the ESI mode were measured by using an Agilent 6224
TOF with LC–MS system. Low- and high-resolution mass spectra
in the FAB mode were recorded with a VG70S spectrometer (Xe-
FAB ionization) by using m-nitrobenzyl alcohol as the matrix. IR
spectra were measured with a Thermo-Nicolet Avatar 370 FTIR
spectrometer or with a Bruker Tensor diamond-ATR FTIR spec-
trometer. Melting points were determined with a Kleinfeld Labor-
technik Apotec apparatus. Microwave reactions were carried out in
a CEM Discover monomode apparatus at the indicated maximum
temperature and power setting.
Scheme 2. Synthesis of quinoline-3-carboxylates from intermedi-
ates 4.
Another route to quinolines converts quinolones 4 into
the corresponding triflates, which can in turn be subjected
to standard Pd-catalyzed coupling reactions. As an exam-
ple, 2,4-diphenylquinoline (9) was prepared from 2-phenyl-
4-quinonole (6a) by DMAP-catalyzed triflylation with Tf2O
in pyridine and subsequent Suzuki coupling with phenyl-
boronic acid (Scheme 3).[14]
Ethyl 3-Cyano-3-phenylamino-3-phenylpropanoate (4a): α-(Phen-
ylamino)phenylacetonitrile[15,20] (500 mg, 2.40 mmol) was dissolved
in THF (20 mL) and cooled to –78 °C. A solution of KHMDS
(527 mg, 2.64 mmol) in THF (10 mL) was added dropwise within
5 min to the stirred solution. Immediately after complete addition
of the base, ethyl bromoacetate (441 mg, 2.64 mmol, 295 µL) in
THF (5 mL) was added. The mixture was allowed to stir for 1.5 h
at –78 °C. Subsequently, the mixture was quenched with saturated
aqueous NaHCO3 solution (10 mL) and extracted with ethyl acet-
ate (20 mL). The organic layer was washed with brine and concen-
trated in vacuo. Purification was carried out by flash chromatog-
raphy (cyclohexane Ǟ cyclohexane/ethyl acetate, 19:1) to yield the
title compound as a colorless oil (613 mg, 2.08 mmol, 87%). Rf =
0.75 (cyclohexane/ethyl acetate, 5:1). 1H NMR (400 MHz, CDCl3):
δ = 7.67–7.65 (m, 2 H, H2Ј,6Ј), 7.44–7.36 (m, 3 H, H3ЈЈ,4ЈЈ,5ЈЈ),
7.13–7.09 (m, 2 H, H3Ј,5Ј), 6.84–6.80 (m, 1 H, H4Ј), 6.57–6.54 (m,
Scheme 3. Conversion of 4-quinolone 6a into quinoline 9.
2 H, H2Ј,6Ј), 5.80 (s, 1 H, NH), 4.27 (dq, 3Jq = 7.2 Hz, 2Jd
=
2
10.8 Hz, 2 H, -OCH2CH3), 3.04 (d, J = 15.4 Hz, 1 H, H2a), 2.49
2
3
(d, J = 15.4 Hz, 1 H, H2b), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3)
ppm. 13C NMR, HSQC, HMBC (100 MHz, CDCl3): δ = 168.9
(C1), 143.5 (C1Ј), 138.3 (C1ЈЈ), 129.5 (C3ЈЈ,5ЈЈ,4ЈЈ), 129.0 (C3Ј,5Ј),
125.5 (C2ЈЈ,6ЈЈ), 120.6 (C4Ј), 118.6 (-CN), 116.9 (C2Ј,6Ј), 61.9
(-OCH2CH3), 59.2 (C3), 48.1 (C2), 14.2 (-OCH2CH3) ppm. MS
(FAB): m/z (%) = 295.1 (85) [M + H]+, 294.1 (100) [M]+, 268.1 (75)
[M – CN]+, 221.1 (7) [M – C3H5O2]+, 207.1 (60) [M – C4H7O2]+,
180.1 (35) [M – CN – C4H7O2]+. HRMS (FAB): calcd. for [M]+
Conclusions
In summary, a modular synthesis of 2-aryl-4-quinolones
from aromatic aldehydes, anilines, and α-bromoesters was
developed. Its key step is the alkylation of a deprotonated
Strecker product, which is followed by a thermal double
elimination. The procedure allows variation at the 2- and
3-positions as well as of the benzoid part of the products.
While attempts to introduce substituents to the 1-position
by using N-substituted anilines as precursors have so far
met with little success, as the final cyclization did not occur
in these cases, the elaboration of the intermediate enamino
esters or final products into quinolines is feasible.
294.1368; found 294.1363. IR (film): ν = 3054, 2986, 2305, 1725,
˜
1498, 1421, 1265, 1191, 895 cm–1.
Ethyl 3-Cyano-3-(4-methylphenylamino)-3-phenylpropanoate (4b): α-
(4-Methylphenylamino)phenylacetonitrile[16] (102 mg, 0.459 mmol)
was dissolved in THF (10 mL) and cooled to –78 °C. KHMDS
(110 mg, 0.551 mmol) was dissolved in THF (5 mL) and added to
the stirred solution within 2 min. Ethyl bromoacetate (48.3 mg,
0.505 mmol, 564 µL) in THF (3 mL) was added immediately after
Eur. J. Org. Chem. 2010, 5841–5849
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5843

A. Romek, T. Opatz
FULL PAPER
deprotonation to the reaction mixture and stirred for 0.5 h at
–78 °C. Aqueous workup was performed according to the pro-
cedure for the preparation of 4a. Purification of the crude product
by flash chromatography (cyclohexane Ǟ cyclohexane/ethyl acet-
ate, 19:1) yielded the title compound as slightly yellowish oil
(98 mg, 0.32 mmol, 70%). Rf = 0.71 (cyclohexane/ethyl acetate,
H, H5Ј), 6.37 (dd, 3J = 8.2 Hz, 4J = 2.2 Hz, 4J = 0.7 Hz, 1 H, H4Ј),
3
4
4
6.16 (dd, J = 8.2 Hz, J = 2.3 Hz, J = 0.7 Hz, 1 H, H6Ј), 6.09 (t,
2
3J = 2.3 Hz, 1 H, H2Ј), 5.84 (s, 1 H, -NH), 4.26 (dq, J = 10.8 Hz,
2
3J = 7.2 Hz, 2 H, -OCH2CH3), 3.62 (s, 3 H, -OCH3), 3.01 (d, J =
3
3
15.4 Hz, 1 H, H2a), 2.95 (d, J = 15.4 Hz, 1 H, H2b), 1.30 (t, J =
7.2 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.2 (C1), 160.6 (C3Ј), 145.1 (C1Ј), 138.4 (C1ЈЈ), 129.9 (C5Ј), 129.6
(C3ЈЈ,5ЈЈ), 129.1 (C4ЈЈ), 125.4 (C2ЈЈ,6ЈЈ), 118.9 (-CN), 109.5 (C6Ј),
106.3 (C4Ј), 102.5 (C2Ј), 62.0 (-OCH2CH3), 59.2 (C3), 55.0
(-OCH3), 48.2 (C2), 14.3 (-OCH2CH3) ppm. MS (ESI): m/z (%) =
325.2 (60) [M + H]+. HRMS (ESI): calcd. for [M + H]+ 325.1474;
1
3
5:1). H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 7.0 Hz, 2 H,
H2ЈЈ,6ЈЈ), 7.43–7.37 (m, 3 H, H3ЈЈ,4ЈЈ,5ЈЈ), 6.92–6.90 (AAЈ-part of
AAЈBBЈ-spin system,
2 H, H3Ј,5Ј), 6.49–6.46 (BBЈ-part of
2
AAЈBBЈ-spin system, 2 H, H2Ј,6Ј), 5.67 (s, 1 H, -NH), 4.25 (dq, J
3
2
= 10.8 Hz, J = 7.2 Hz, 2 H, -OCH2CH3), 3.00 (d, J = 15.4 Hz, 1
H, H2a), 2.95 (d, 2J = 15.4 Hz, 1 H, H2b) 2.19 (s, 3 H, -CH3), found 325.1475. IR (film): ν = 3365, 2983, 2359, 1728, 1603, 1520,
˜
3
1.29 (t, J = 7.1 Hz, 3 H, -OCH2CH3) ppm. 13C NMR (100 MHz, 1492, 1164, 1037, 765 cm–1.
CDCl3):
δ = 169.1 (C1), 141.4 (C1Ј), 138.4 (C1ЈЈ), 129.6
Ethyl 3-Cyano-3-(3-chlorphenylamino)-3-phenylpropanoate (4e): α-
(3-Chlorophenylamino)phenylacetonitrile (3e;[16,18] 100 mg, 0.41
mmol) was dissolved in THF (10 mL) and cooled to –78°. To the
stirred solution was added KHMDS (90 mg, 0.45 mmol) in THF
(5 mL) within 2 min. Ethyl bromoacetate (75.3 mg, 0.450 mmol,
50.4 µL) in THF (3 mL) was added, and the mixture was allowed
to stir for 0.5 h at –78 °C. Workup was performed according to
the procedure for the preparation of 4a. Flash chromatographic
(C3ЈЈ,4ЈЈ,5ЈЈ), 129.5 (C2Ј,6Ј), 129.3 (C4ЈЈ), 125.5 (C2ЈЈ,6ЈЈ), 122.4
(C4Ј), 118.9 (-CN), 116.9 (C2Ј,6Ј), 62.0 (-OCH2CH3), 59.4 (C3),
47.2 (C2), 20.6 (-CH3), 14.3 (-OCH2CH3) ppm. MS (FAB): m/z (%)
= 309 (55) [M + H]+, 308 (100) [M]+, 282 (64) [M – CN]+, 235 (8)
[M – C3H5O2]+, 221 (63) [M – C4H7O2]+, 194 (41) [M – CN –
C4H7O2]+. HRMS (FAB): calcd. for [M]+ 308.1525; found
308.1525. IR (film): ν = 3358, 2983, 1727, 1655, 1518, 1265, 1217,
˜
1190, 737, 700 cm–1.
purification (cyclohexane
Ǟ cyclohexane/ethyl acetate, 99:1)
Ethyl 3-Cyano-3-(4-methoxyphenylamino)-3-phenylpropanoate (4c): yielded compound 4e as a slightly yellow oil (111 mg, 0.340 mmol,
To a stirred solution of α-(4-methoxyphenylamino)phenylacetoni-
trile (3c;[16,17] 500 mg, 2.10 mmol) in THF (20 mL) was dropwise
added a solution of KHMDS (461 mg, 2.31 mmol) in THF (10 mL)
within 5 min at –78 °C. Ethyl bromoacetate (386 mg, 2.31 mmol,
258 µL) in THF (3 mL) was added, and the reaction mixture was
stirred for 2 h at –78 °C. Aqueous workup was performed accord-
ing to the procedure for the preparation of 4a, and purification by
flash chromatography (cyclohexane Ǟ cyclohexane/ethyl acetate,
8:2) yielded the title compound as an orange oil (462 mg,
1.43 mmol, 67%). Rf = 0.73 (cyclohexane/ethyl acetate, 5:1). 1H
83%). Rf = 0.45 (cyclohexane/ethyl acetate, 2:1). 1H NMR
(400 MHz, CDCl3): δ = 7.64–7.61 (m, 2 H, H2ЈЈ,6ЈЈ), 7.45–7.39 (m,
3 H, H3ЈЈ,4ЈЈ,5ЈЈ), 7.00 (t, J = 8.2 Hz, 1 H, H5Ј), 6.78 (dd, J =
3
3
4
4
4
7.9 Hz, J = 2.1 Hz, J = 0.8 Hz, 1 H, H4Ј), 6.59 (t, J = 2.1 Hz, 1
H, H2Ј), 6.37 (dd, 3J = 8.2 Hz, 4J = 2.1 Hz, 3J = 0.8 Hz, 1 H, H6Ј),
5.96 (s, 1 H, -NH), 4.26 (dq, 2Jd = 8.6 Hz, 3Jq = 8.6 Hz, 2 H,
-OCH2CH3), 3.02 (d, 2J = 15.4 Hz, 1 H, H2a), 2.93 (d, 2J =
3
15.4 Hz, 1 H, H2b), 1.30 (t, J = 7.2 Hz, 3 H, -OCH2CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.7 (C1), 145.3 (C3Ј), 137.9
(C1ЈЈ), 134.8 (C1Ј), 129.9 (C5Ј), 129.6 (C3ЈЈ,5ЈЈ), 129.3 (C4ЈЈ), 127.1
(C4Ј), 125.5 (C2ЈЈ,6ЈЈ), 120.5 (C4Ј), 118.4 (-CN), 117.0 (C2Ј), 114.5
(C6Ј), 62.5 (-OCH2CH3), 58.9 (C3), 48.0 (C2), 14.1 (-OCH2CH3)
3
NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.2 Hz, 2 H, H6ЈЈ,2ЈЈ),
7.44–7.38 (m, 3 H, H3ЈЈ,4ЈЈ,5ЈЈ), 6.69–6.67 (AAЈ part of AAЈBBЈ
spin system, 2 H, H3Ј,5Ј), 6.53–6.51 (BBЈ part of AAЈBBЈ spin ppm. MS (ESI): m/z (%) = 351.1 (30) [M + Na]+, 329.1 (100) [M
system, 2 H, H2Ј,6Ј), 5.57 (s, 1 H, -NH), 4.25 (dq, 3Jq = 7.2 Hz, + H]+. HRMS (ESI): calcd. for [M + H]+ 329.1061; found
2Jd = 10.8 Hz, 2 H, -OCH2CH3), 3.69 (s, 3 H, -OCH3), 2.98 (s, 2
H, H2), 1.30 (t, 3J = 7.2 Hz, 3 H, -OCH2CH3) ppm. The 1H NMR
spectrum showed trace amounts of unreacted starting material 3c.
13C NMR (100 MHz, CDCl3): δ = 169.4 (C1), 154.1 (C4Ј), 138.2
(C1Ј), 137.0 (C1ЈЈ), 129.4 (C3ЈЈ,5ЈЈ), 128.9 (C4ЈЈ), 118.9 (C3Ј,5Ј),
119.2 (-CN), 114.4 (C2Ј,6Ј), 62.1 (-OCH2CH3), 59.9 (C3), 55.5
(-OCH3), 47.8 (C2), 14.0 (-OCH2CH3) ppm. MS (FAB): m/z (%) =
325.3 (35) [M + H]+, 324.3 (100) [M]+, 198.3 (40) [M – CN]+, 237.2
[M – C4H7O2], 210.2 [M – C4H7O2–CN]. HRMS (FAB): calcd. for
329.1051. IR (film): ν = 3358, 3054, 2986, 2359, 1724, 1598, 1265,
˜
1218, 739, 704 cm–1.
Ethyl 3-Cyano-3-phenylamino-3-(4-methoxyphenyl)propanoate (4f):
A solution of KHMDS (94.4 mg, 0.473 mmol) in THF (5 mL) was
added within 3 min to a stirred solution of α-(phenylamino)-4-
methoxyphenylacetonitrile (3f;[16,19] 102 mg, 0.430 mmol) in THF
(10 mL) at –78 °C. Ethyl bromoacetate (77.9 mg, 0.473 mmol,
53.5 µL) in THF (3 mL) was added immediately after addition of
the KHMDS solution, and the mixture was allowed to stir for 1 h
at –78 °C. Workup was performed according to the procedure for
the preparation of 4a. The crude product was purified by flash
[M]+ 324.1474; found 324.1489 ppm. IR (film): ν = 3054, 2986,
˜
2305, 1727, 1513, 1265, 1216, 1035, 738, 703 cm–1.
Ethyl 3-Cyano-3-(3-methoxyphenylamino)-3-phenylpropanoate (4d): chromatography (cyclohexane Ǟ cyclohexane/ethyl acetate, 4:1) to
α-(3-Methoxyphenylamino)phenylacetonitrile (3d;[17,18] 105 mg,
0.441 mmol) was dissolved in THF (10 mL) and cooled to –78 °C.
KHMDS (96 mg, 0.49 mmol) in THF (5 mL) was added within
2 min to the stirred solution. Subsequently, ethyl bromoacetate
(80.2 mg, 0.485 mmol, 53.7 µL) in THF (3 mL) was added to the
mixture, which was stirred for 3.5 h at –78 °C. The reaction was
quenched with saturated aqueous NaHCO3 solution (5 mL) and
extracted with ethyl acetate (10 mL). The organic layer was washed
with brine and concentrated in vacuo. Purification of the crude
product by flash chromatography (cyclohexane Ǟ cyclohexane/
yield the title compound as a colorless oil (46 mg, 0.14 mmol,
33%). Rf = 0.42 (cyclohexane/ethyl acetate, 2:1). 1H NMR
(400 MHz, CDCl3): δ = 7.56–7.54 (AAЈ part of the AAЈBBЈ spin
system, 2 H, H2ЈЈ,6ЈЈ), 7.11 (dd, 3J = 8.3 Hz, 3J = 7.7 Hz, 2 H,
H3Ј,5Ј), 6.93–6.91 (BBЈ part of the AAЈBBЈ spin system, 2 H,
H3ЈЈ,5ЈЈ), 6.82 (t, 3J = 7.4 Hz, 1 H, H4Ј), 6.57 (d, 3J = 7.7 Hz, 2 H,
H2Ј,6Ј), 5.75 (s, 1 H, -NH), 4.25 (dq, 2Jd = 10.2 Hz, 3Jq = 7.2 Hz, 2
2
H, -OCH2CH3), 3.82 (s, 3 H, -OCH3), 2.99 (d, J = 15.4 Hz, 1 H,
3
H2a), 2.94 (d, 2J = 15.4 Hz, 1 H, H2b), 1.30 (t, J = 7.2 Hz, 3 H, -
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2 (C1),
ethyl acetate, 19:1) yielded the title compound as a colorless oil 160.3 (C4ЈЈ), 143.6 (C1Ј), 130.2 (C1ЈЈ), 129.0 (C3Ј,5Ј), 126.9
(76 mg, 0.24 mmol, 55%). Rf = 0.48 (cyclohexane/ethyl acetate,
(C3ЈЈ,5ЈЈ), 120.9 (C4Ј), 118.9 (-CN), 116.8 (C2Ј,6Ј), 114.6 (C2ЈЈ,6ЈЈ),
2:1). 1H NMR (400 MHz, CDCl3): δ = 7.67–7.65 (m, 2 H, 62.1 (-OCH2CH3), 60.2 (C3), 55.6 (-OCH3), 48.4 (C2), 14.3
H2ЈЈ,6ЈЈ), 7.44–7.36 (m, 3 H, H3ЈЈ,4ЈЈ,5ЈЈ), 7.01 (t, 3J = 8.2 Hz, 1 (-OCH2CH3) ppm. MS (ESI): m/z (%) = 325.2 (100) [M + H]+.
5844
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5841–5849

Polysubstituted 4-Quinolones from Deprotonated α-Aminonitriles
HRMS (ESI): calcd. for [M + H]+ 325.1547; found 325.1550. IR
309.2 (65) [M + H]+. HRMS (ESI): calcd. for [M]+ 308.1525; found
(film): ν = 2980, 2359, 1731, 1605, 1510, 1254, 1175, 1030,
308.1526. IR (film): ν = 3386, 2983, 2359, 1720, 1603, 1499, 1190,
˜
˜
752 cm–1.
752 cm–1.
Ethyl 3-Cyano-3-phenylamino-3-(2-chlorophenyl)propanoate (4g): To
a solution of α-(phenylamino)-2-chlorophenylacetonitrile (3g;[16,18]
100 mg, 0.412 mmol) in THF (10 mL) was added KHMDS
(89.8 mg, 0.453 mmol) in THF (5 mL) dropwise within 2 min at
–78 °C. Ethyl bromoacetate (75.3 mg, 0.453 mmol, 50.4 µL) in
THF (3 mL) was added to the mixture, which was then stirred for
1 h at –78 °C. Workup was performed according to the procedure
for the preparation of 4a. Purification was achieved by flash
chromatography (cyclohexane Ǟ cyclohexane/ethyl acetate, 19:1)
to yield the title compound as a colorless oil (84 mg, 0.25 mmol,
61%). Rf = 0.41 (cyclohexane/ethyl acetate, 2:1). 1H NMR
(400 MHz, CDCl3): δ = 7.72 (dd, 3J = 7.8 Hz, 4J = 1.3 Hz, 1 H,
Ethyl 3-Cyano-2-ethyl-3-phenylamino-3-phenylpropanoate (4i): A
solution of KHMDS (105 mg, 0.528 mmol) in THF (5 mL) was
added within 3 min to a stirred solution of α-(phenylamino)phenyl-
acetonitrile (3a;[15,20] 99.4 mg, 0.480 mmol) in THF (10 mL) at
–78 °C. Ethyl bromobutyrate (0.528 mmol, 77.4 µL) in THF (3 mL)
was added, and the mixture was stirred for 1 h at –78 °C. Workup
was performed according to the procedure for the preparation of
4a. Purification of the crude product by flash chromatography (cy-
clohexane Ǟ cyclohexane/ethyl acetate, 49:1) gave the title com-
pound as a colorless oil (95 mg, 0.30 mmol, 63%). Ratio of dia-
1
stereomers: A/B = 10:3, determined by H NMR spectroscopy. Rf
= 0.67 (cyclohexane/ethyl acetate, 5:1). 1H NMR (400 MHz,
3
3
3
3
3
H3ЈЈ), 7.46 (dd, J = 7.8 Hz, J = 0.9 Hz, 1 H, H6ЈЈ), 7.33 (dt, J CDCl3): δ = 7.58 (d, J = 6.5 Hz, 2 H, H2ЈЈB,6ЈЈB), 7.52 (d, J =
= 7.8 Hz, 4J = 1.5 Hz, 1 H, H4ЈЈ), 7.28 (dd, 3J = 7.8 Hz, 4J =
6.8 Hz, 2 H, H2ЈЈA,6ЈЈA), 7.40–7.33 (m, 6 H, H3ЈЈA,4ЈЈA,5ЈЈA, over-
lap of signals with H3ЈЈB,4ЈЈB,5ЈЈB), 7.09 (t, 3J = 7.7 Hz, 4 H,
3
3
0.9 Hz, 1 H, H5ЈЈ), 7.13 (t, J = 7.5 Hz, 2 H, H3Ј,5Ј), 6.82 (t, J =
3
3
7.5 Hz, 1 H, H4Ј), 6.56 (d, J = 7.5 Hz, 2 H, H2Ј,6Ј), 5.74 (s, 1 H,
H3ЈA,5ЈA, overlap of signals with H3ЈB,5ЈB), 6.80 (t, J = 7.6 Hz, 1
-NH), 4.21 (m, 2 H, -OCH2CH3), 3.42 (d, 2J = 14.9 Hz, 1 H, H2a), H, H4ЈB), 6.75 (t, J = 7.3 Hz, 1 H, H4ЈA), 6.55 (d, J = 8.1 Hz, 2
3
3
3.12 (d, 2J = 14.9 Hz, 1 H, H2b), 1.25 (t, 3J = 7.1 Hz, 3 H, H, H2ЈA,6ЈA), 6.54–6.53 (m, 4 H, H2ЈB,6ЈB, overlap of signals with
1
2
-OCH2CH3) ppm. The H NMR spectrum showed trace amounts
H2ЈA,6ЈA), 5.62 (s, 1 H, -NHB), 5.37 (s, 1 H, -NHA), 4.27 (dq, J
= 10.7 Hz, J = 6.9 Hz, 2 H, -OCH2CH3B), 4.08 (dq, 2J = 10.3 Hz,
3
of impurities due to the decomposition of 4g during flash
chromatography. 13C NMR (100 MHz, CDCl3): δ = 168.0 (C1),
3J = 7.2 Hz, 2 H, -OCH2CH3A), 2.83 (dd, 2J = 12.0 Hz, 3J =
142.3 (C1Ј), 132.1 (C6ЈЈ), 131.2 (C2ЈЈ), 130.7 (C1ЈЈ), 129.6 (C4ЈЈ), 3.0 Hz, 2 H, H2A, overlap of signals with H2B), 2.10 (dq, 3J =
128.7 (C3ЈЈ), 128.1 (C3Ј,5Ј), 126.7 (C5ЈЈ), 119.5 (C4Ј), 116.5 (-CN), 7.1 Hz, 2 H, -CH2CH3A), 1.93–1.76 (m, 2 H, -CH2CH3B), 1.32 (t,
3
115.5 (C2Ј,6Ј), 61.1 (-OCH2CH3), 56.7 (C3), 42.6 (C2), 13.1
3J = 7.1 Hz, 3 H, -OCH2CH3B), 1.10 (t, J = 7.1 Hz, 3 H, -OCH2-
(-OCH2CH3) ppm. MS (ESI): m/z (%) = 351.1 (10) [M + Na]+, CH3A), 0.93 (t, 3J = 7.3 Hz, 3 H, -CH2CH3A), 0.83 (t, 3J = 7.4 Hz,
329.1 (100) [M + H]+. HRMS (ESI): calcd. for [M + H]+ 329.1051; 3 H, -CH2CH3B) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9
found 329.1058. IR (film): ν = 3380, 2982, 2360, 1727, 1603, 1498, (C1B), 171.8 (C1A), 143.2 (C1ЈA,B), 137.1 (C1ЈЈA), 135.6 (C1ЈЈB),
˜
1213, 753, 737 cm–1.
129.1 (C3ЈB,4ЈB,5ЈB), 129.0 (C3ЈЈA,4ЈЈA,5ЈЈA), 128.9 (C3ЈA,5ЈA),
128.8 (C3ЈB,5ЈB), 126.5 (C2ЈЈB,6ЈЈB), 125.8 (C2ЈЈA,6ЈЈA), 119.9
(C4ЈB), 119.3 (C4ЈA), 118.9 (-CNB), 118.2 (-CNA), 116.3 (C2ЈB,6ЈB),
115.4 (C2ЈA,6ЈA), 62.7 (C3A,B), 61.9 (-OCH2CH3B), 61.5 (-OCH2-
CH3A), 59.2 (C2A), 58.1 (C2B), 22.0 (-CH2CH3A,B), 14.2
(-OCH2CH3B), 14.1 (-OCH2CH3A), 11.9 (-CH2CH3A), 11.6
(-CH2CH3B) ppm. MS (ESI): m/z (%) = 345.2 (30) [M + Na]+,
323.2 (100) [M + H]+. HRMS (ESI): calcd. for [M + H]+ 323.1754;
Ethyl 3-Cyano-2-methyl-3-phenylamino-3-phenylpropanoate (4h): α-
(Phenylamino)phenylacetonitrile (3a;[15,20] 99.7 mg, 0.479 mmol)
was dissolved in THF (10 mL) and a solution of KHMDS (105 mg,
0.527 mmol) in THF (5 mL) was added at –78 °C within 2 min.
Ethyl bromopropionate (95.9 mg, 0.527 mmol, 69.1 µL) in THF
(3 mL) was added, and the reaction mixture was stirred for 2 h at
–78 °C. Workup was performed according to the procedure for the
preparation of 4a. Purification of the crude product by flash
chromatography (cyclohexane Ǟ cyclohexane/ethyl acetate, 19:1)
gave the title compound as a colorless oil (80 mg, 0.26 mmol, 54%).
found 323.1764. IR (ATR): ν = 3341, 1652, 1634, 1597, 1522, 1434,
˜
1254, 748, 688, 642 cm–1.
Ethyl 3-Cyano-2,3-diphenyl-3-phenylaminopropanoate (4j): α-(Phen-
ylamino)phenylacetonitrile (3a;[15,20] 100 mg, 0.480 mmol) was dis-
solved in THF (10 mL) and a solution of KHMDS (106 mg,
0.528 mmol) in THF (5 mL) was added within 2 min while stirring
1
Ratio of diastereomers A/B = 10:7, determined by H NMR spec-
troscopy. Rf = 0.62 (cyclohexane/ethyl acetate, 5:1). 1H NMR
(400 MHz, CDCl3): δ = 7.59–7.56 (m, 4 H, H3ЈЈA,5ЈЈA, overlap of
signals with H3ЈЈB,5ЈЈB), 7.42–7.34 (m, 6 H, H2ЈЈA,4ЈЈA,6ЈЈA, over- at –78 °C. Ethyl α-bromophenylacetate (128 mg, 0.528 mmol,
lap of signals with H2ЈЈB,4ЈЈB,6ЈЈB), 7.12–7.06 (m, 4 H, H3ЈA,5ЈA,
92.4 µL) in THF (3 mL) was added, and the mixture was stirred
for 4 h at –78 °C. Workup was performed according to the pro-
3
overlap of signals with H3ЈB,5ЈB), 6.80 (t, J = 7.4 Hz, 1 H, H4ЈB),
6.77 (t, 3J = 7.4 Hz, 1 H, H4ЈA), 6.54 (d, 3J = 7.9 Hz, 4 H, cedure for the preparation of 4a. Purification of the crude product
H2ЈA,6ЈA, overlap of signals with H2ЈB,6ЈB), 5.63 (s, 2 H, -NHA,
by flash chromatography (cyclohexane Ǟ cyclohexane/ethyl acet-
overlap of the signal with -NHB), 4.31–4.24 (m, 2 H, -OCH2CH3B),
ate, 19:1) yielded the title compound as a light yellow oil (57 mg,
3
1
4.21–4.12 (m, 2 H, -OCH2CH3A), 3.06 (q, J = 7.2 Hz, 2 H, H3B), 0.15 mmol, 32%). Both diastereomers could be separated. The H
3
A
3.00 (q, J = 7.2 Hz, 2 H, H3A), 1.31–1.29 (m, 6 H, -OCH2CH3
NMR spectrum of the less mobile diastereomer showed impurities
that could not be removed by flash chromatography. The more mo-
,
overlap of signals with -CH3B), 1.22–1.18 (m, 6 H, -CH3A, ppm,
overlap of signals with -OCH2CH3B). The 1H NMR spectrum
shows trace amounts of impurities due to decomposition during
flash chromatography. 13C NMR (100 MHz, CDCl3): δ = 172.0
(C1B), 170.9 (C1A), 141.8 (C1ЈA,B), 135.4 (C1ЈЈA,B), 129.3
bile diastereomer was obtained as
a colorless oil (50 mg,
0.13 mmol, 27%), showing no impurities in its 1H NMR spectrum.
Rf (diastereomer 1) = 0.42 (cyclohexane/ethyl acetate, 2:1). 1H
NMR (400 MHz, CDCl3, diastereomer 1): δ = 7.53–7.51 (m, 2 H,
(C2ЈЈB,6ЈЈB), 129.3 (C4ЈЈB), 129.2 (C4ЈЈA), 129.1 (C2ЈЈA,6ЈЈA), 129.0 H2ЈЈЈ,6ЈЈЈ), 7.41–7.38 (m, 2 H, H2ЈЈ,6ЈЈ), 7.37–7.30 (m, 6 H,
(C3ЈA,B,5ЈA,B), 126.8 (C3ЈЈB,5ЈЈB), 126.3 (C3ЈЈA,5ЈЈA), 120.2 (C4ЈB),
120.0 (C4ЈA), 118.0 (-CNA,B), 116.5 (C2ЈB,6ЈB), 116.0 (C2ЈA,6ЈA),
63.6 (C3A,B), 62.0 (-OCH2CH3B), 61.9 (-OCH2CH3A), 51.2 (C2A),
H3ЈЈ,4ЈЈ,5ЈЈ,3ЈЈЈ,4ЈЈЈ,5ЈЈЈ), 7.06–7.01 (m, 2 H, H3Ј,5Ј), 6.80–6.75 (m,
3
4
1 H, H4Ј), 6.46 (d, J = 8.6, J = 0.9 Hz, 2 H, H2Ј,6Ј), 5.24 (s, 1
H, -NH), 4.22–3.99 (m, 3 H, -OCH2CH3, H2), 1.12 (t, 3J = 7.3 Hz,
50.7 (C2B), 14.2 (-CH3B), 14.1 (-CH3A), 13.5 (-OCH2CH3A), 12.0 3 H, -OCH2CH3) ppm. Rf (diastereomer 2) = 0.51 (cyclohexane/
(-OCH2CH3B) ppm. MS (ESI): m/z (%) = 331.2 (25) [M + Na]+,
ethyl acetate, 2:1). 1H NMR (400 MHz, CDCl3, diastereomer 2,
Eur. J. Org. Chem. 2010, 5841–5849
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5845

A. Romek, T. Opatz
FULL PAPER
COSY): δ = 7.36 (dd, 3J = 7.9 Hz, 3J = 1.8 Hz, 2 H, H2ЈЈЈ,6ЈЈЈ), (C5), 123.2 (C8), 118.7 (C7), 107.3 (C3) ppm. MS (FAB): m/z (%)
7.31–7.27 (m, 2 H, H2ЈЈ,6ЈЈ), 7.25–7.22 (m, 3 H, H3ЈЈ,4ЈЈ,5ЈЈ), 7.20– = 222.1 (100) [M]+. HRMS (FAB): calcd. for [M]+ 222.0919; found
7.17 (m, 3 H, H3ЈЈЈ,4ЈЈЈ,5ЈЈЈ), 7.07–7.05 (m, 2 H, H3Ј,5Ј), 6.77 (t, 222.0919. IR (ATR): ν = 1633, 1545, 1498, 1472, 1254, 753,
˜
3
3J = 7.3 Hz, 1 H, H4Ј), 6.54 (d, J = 7.7 Hz, 2 H, H2Ј,6Ј), 5.46 (s,
688 cm–1. The analytical data correspond to those reported in the
1 H, -NH), 4.19 (q, 3J = 7.1 Hz, 2 H, -OCH2CH3), 4.05 (s, 1 H, literature.[25,26]
H2), 1.17 (t, 3J = 7.1 Hz, 3 H, -OCH2CH3) ppm. 13C NMR
6-Methyl-2-phenyl-1H-quinolin-4-one (6b): Aminonitrile 4b (91 mg,
(100 MHz, CDCl3, diastereomer 2, HMBC, HSQC): δ = 170.9
(C1), 149.7 (C1Ј), 136.7 (C1ЈЈ), 131.9 (C1ЈЈЈ), 129.8 (C4ЈЈ), 128.7
(C3ЈЈЈ,5ЈЈЈ), 128.2 (C2ЈЈЈ,6ЈЈЈ), 126.7 (C3Ј,5Ј), 126.3 (C2ЈЈ,6ЈЈ), 120.2
(C4Ј), 118.8 (-CN), 116.7 (C2Ј,6Ј), 64.2 (C3), 62.8 (-OCH2CH3),
40.5 (C2), 13.3 (-OCH2CH3) ppm. The resonances of C3ЈЈ, 4ЈЈ, and
5ЈЈ could not be assigned. MS (ESI): m/z (%) = 371.2 (50) [M +
H]+. HRMS (ESI): calcd. for [M + H]+ 370.1681; found 370.1679.
0.30 mmol) was dissolved in diphenyl ether (1.5 mL) and heated
for 15 min to 250 °C. The product was precipitated with n-hexane
(1 mL), centrifuged, and decanted. The crude product was washed
four times with n-hexane (1 mL) to remove the diphenyl ether com-
pletely, yielding the title compound as a colorless solid (50 mg,
0.21 mmol, 71%). M.p. 289–293 °C (ref.[24] 282–293 °C). H NMR
1
(400 MHz, [D6]DMSO): δ = 11.6 (s, 1 H, -NH), 7.89 (m, 1 H, H5),
7.83 (dd, 3J = 6.5 Hz, 3J = 3.7 Hz, 2 H, H2Ј,6Ј), 7.67 (d, 3J =
8.5 Hz, 1 H, H8), 7.60–7.57 (m, 3 H, H3Ј,4Ј,5Ј), 7.50 (dd, 3J =
8.5 Hz, 4J = 1.9 Hz, 1 H, H7), 6.31 (s, 1 H, H3), 2.97 (s, 3 H,
-CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.4 (C4),
154.7 (C2), 141.0 (C4a), 135.6 (C1Ј), 133.0 (C7), 132.5 (C8a), 130.2
(C4Ј), 128.9 (C3Ј,5Ј), 127.2 (C2Ј,6Ј), 123.9 (C5), 119.1 (C7), 107.3
(C3), 20.7 (-CH3) ppm. MS (FAB): m/z (%) = 237.2 (20) [M +
H]+, 236.2 (100) [M]+. HRMS (FAB): calcd. for [M]+ 236.107539;
IR (film): ν = 3352, 2360, 1739, 1606, 1502, 1448, 1205, 685 cm–1.
˜
Ethyl 3-(Phenylamino)cinnamate (5a): The reaction was carried out
under microwave irradiation with a maximum power of 300 W by
using air cooling. To aminonitrile 4a (104 mg, 0.353 mmol) was
added DBU (59.2 mg, 0.389 mmol, 58.6 µL, 1.1 equiv.), and the
mixture was heated for 15 min to 100 °C. Purification was carried
out by filtration through silica (cyclohexane) to yield the title com-
pound as a colorless oil (71.4 mg, 0.267 mmol, 77%). The ratio of
E/Z isomers was 1:3, as determined by 1H NMR spectroscopy. The
NMR signals were assigned by comparison with literature data.[23]
Rf = 0.21 (cyclohexane/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3): δ = 12.56 (s, 1 H, -NHE), 10.28 (s, 1 H, -NHZ), 7.93 (d,
found 236.107128. IR (ATR): ν = 3067, 2957, 1635, 1543, 1498,
˜
823, 770, 691 cm–1. The analytical data correspond to those re-
ported in the literature.[25,27]
6-Methoxy-2-phenyl-1H-quinolin-4-one (6c): Cyclization of amino-
nitrile 4c (50 mg, 0.15 mmol) in diphenyl ether (2 mL) was effected
by heating the mixture at 250 °C for 10 min. Subsequently, the
product was precipitated with n-hexane (1 mL), centrifuged, de-
canted, and washed four times with n-hexane (1 mL) to furnish
quinolone 6c as a slightly brownish solid (28 mg, 0.11 mmol, 73%).
M.p. 309–311 °C (ref.[25] 302–304 °C). 1H NMR (400 MHz, [D6]-
DMSO): δ = 11.70 (s, 1 H, -NH), 7.85–7.79 (m, 2 H, H2Ј,6Ј), 7.73
3J = 7.5 Hz, 2 H, H2ЈE,6ЈE), 7.58 (t, J = 7.4 Hz, 1 H, H4ЈE), 7.47
3
(t, 3J = 7.6 Hz, 2 H, H3ЈE,5ЈE), 7.34–7.29 (m, 3 H, H3ЈЈZ,4ЈЈZ,5ЈЈZ,
overlap of signals with H3ЈЈE,4ЈЈE,5ЈЈE), 7.29–7.25 (m, 2 H,
H2ЈЈZ,6ЈЈZ, overlap of signals with 2ЈЈE,6ЈЈE), 7.08–7.03 (m, 2 H,
H3ЈZ,5ЈZ), 6.91–6.86 (m, 1 H, H4ЈZ), 6.65–6.62 (m, 2 H, H2ЈZ,6ЈZ),
4.97 (s, 1 H, H2Z), 4.19 (q, J = 7.1 Hz, 2 H, -OCH2CH3E,Z), 3.97
3
(s, 1 H, H2E), 1.30 (t, J = 7.1 Hz, 3 H, -OCH2CH3Z), 1.24 (t, J
= 7.1 Hz, 3 H, -OCH2CH3E) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.3 (C1Z), 167.8 (C1E), 159.3 (C3Z), 140.7 (C1ЈE), 140.5
(C1ЈZ), 136.2 (C1ЈЈZ), 133.9 (C4E), 129.6 (C3ЈE,5ЈE), 129.0
(C2ЈE,6E), 128.9 (C3ЈZ,5ЈZ), 128.7 (C2ЈЈE,6ЈЈE), 128.7 (C4ЈЈZ), 128.6
(C3ЈЈZ,5ЈЈZ), 128.4 (C2ЈЈZ,6ЈЈZ), 123.6 (C3ЈЈE,5ЈЈE), 123.1 (C4ЈZ),
121.4 (C4ЈЈE), 122.3 (C2ЈZ,6ЈZ), 91.3 (C2Z), 61.6 (-OCH2CH3E),
59.5 (-OCH2CH3Z), 46.1 (C2E), 14.6 (-OCH2CH3Z), 14.2 (-OCH2-
CH3E) ppm. The resonances of C1ЈЈE and C3E could not be de-
tected. MS (ESI): m/z (%) = 268.1 (25) [M + H]+, 222.1 (100) [M –
C2H5O]+. HRMS (ESI): calcd. for [M + H]+ 268.1332; found
3
3
3
4
(d, J = 8.9 Hz, 1 H, H8), 7.58 (m, 3 H, H3Ј,4Ј,5Ј), 7.51 (d, J =
2.5 Hz, 1 H, H5), 7.33 (dd, 3J = 8.9 Hz, 4J = 2.5 Hz, 1 H, H7),
6.32 (s, 1 H, H3), 3.85 (s, 3 H, -OCH3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 176.6 (C4), 156.9 (C8a), 155.2 (C6), 134.6 (C1Ј),
133.4 (C4a), 130.3 (C2), 129.4 (C2Ј,6Ј), 127.3 (C3Ј,5Ј), 126.5 (C4Ј),
123.9 (C8), 122.2 (C7), 104.7 (C5), 100.6 (C3), 55.2 (-OCH3) ppm.
MS (ESI): m/z (%) = 252.1 (100) [M + H]+. HRMS (ESI): calcd.
for [M + H]+ 252.1019; found 252.1022. IR (ATR): ν = 1631, 1594,
˜
1579, 1497, 869, 838, 671 cm–1. The analytical data correspond to
those reported in the literature.[25]
268.1330. IR (film): ν = 2978, 1658, 1615, 1596, 1574, 1503, 1484,
˜
1286, 1174, 1039, 769 cm–1. The analytical data correspond to
those reported in the literature.[23]
7-Methoxy-2-phenyl-1H-quinolin-4-one (6d):
A solution of 4d
(76 mg, 0.23 mmol) in diphenyl ether (1.5 mL) was heated to
250 °C for 20 min, yielding a light brown solid, which was tritu-
rated with n-hexane (1 mL), decanted, and centrifuged. The crude
product was washed four times with n-hexane (1 mL), yielding the
title compound as a colorless solid (22 mg, 0.088 mmol, 81%). M.p.
286 °C (ref.[25] 284–286 °C). 1H NMR (400 MHz, [D6]DMSO): δ =
Synthesis of 2-Phenyl-1H-quinolin-4-ones: The following reactions
were carried out in sealed reaction vessels under microwave irradia-
tion with a maximum power of 300 W by using air cooling.
2-Phenyl-1H-quinolin-4-one (6a): Aminonitrile 4a was dissolved in
diphenyl ether (2 mL) and heated for 15 min to 250 °C. The prod-
uct was precipitated with n-hexane and separated by centrifugation
and decantation. To remove the remaining diphenyl ether, the prod-
uct was washed four times with n-hexane (1 mL), yielding the title
compound as a colorless solid (25 mg, 0.11 mmol, 72%). M.p. 251–
253 °C (ref.[24] 251–253 °C). 1H NMR (400 MHz, [D6]DMSO): δ =
3
11.53 (s, 1 H, -NH), 7.99 (d, J = 8.9 Hz, 1 H, H5), 7.83–7.81 (m,
2 H, H2Ј,6Ј), 7.60–7.57 (m, 3 H, H3Ј,4Ј,5Ј), 7.21 (d, J = 2.4 Hz, 1
4
3
4
H, H8), 6.94 (dd, J = 8.9 Hz, J = 2.4 Hz, 1 H, H6), 6.27 (s, 1 H,
H3), 3.87 (s, 3 H, -OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 176.8 (C4), 162.5 (C7), 149.9 (C2), 142.3 (C8a), 134.5 (C1Ј),
130.2 (C4Ј), 128.8 (3,5Ј), 127.4 (C2Ј,6Ј), 126.8 (C5), 119.8 (C4a),
113.4 (C6), 107.4 (C3), 100.4 (C8), 55.33 (-OCH3) ppm. MS (ESI):
m/z (%) = 252.1 (100) [M + H]+. HRMS (ESI): calcd. for [M +
3
4
11.72 (s, 1 H, -NH), 8.10 (dd, J = 8.1 Hz, J = 1.1 Hz, 1 H, H5),
7.84 (dd, 3J = 6.7 Hz, 4J = 3.0 Hz, 2 H, H2Ј,6Ј), 7.77 (d, 3J =
H]+ 252.1019; found 252.1022. IR (ATR): ν = 2965, 1610, 1577,
˜
3
3
4
7.9 Hz, 1 H, H7), 7.67 (dd, J = 8.4 Hz, J = 6.9 Hz, J = 1.6 Hz,
1 H, H6), 7.61–7.57 (m, 3 H, H3Ј,4Ј,5Ј), 7.36–7.32 (m, 1 H, H8),
6.35 (s, 1 H, H3) ppm. 13C NMR (100 MHz, [D6]DMSO, HSQC,
1537, 1460, 1250, 854, 838, 699 cm–1. The analytical data corre-
spond to those reported in the literature.[25,26]
HMBC): δ = 166.3 (C4), 150.0 (C2), 140.9 (C8a), 134.2 (C1Ј), 131.7 7-Chloro-2-phenyl-1H-quinolin-4-one (6e): α-Aminonitrile 4e
(C6), 130.4 (C4Ј), 129.0 (5Ј, C3Ј), 127.3 (6Ј, C2Ј), 124.9 (C4a), 124.6 (45 mg, 0.14 mmol) was dissolved in diphenyl ether (1.5 mL) and
5846
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5841–5849

Polysubstituted 4-Quinolones from Deprotonated α-Aminonitriles
heated for 20 min to 250 °C. Precipitation with n-hexane as de-
scribed for the synthesis of 6a gave the title compound as a color-
less solid (30 mg, 0.12 mmol, 86%) consisting of the regioisomers
6e and 5-chloro-1H-quinolin-4-one (6k) in a ratio of 5:1 deter-
mined by intensity of proton signals in the 1H NMR spectrum (A/
B = 5:1). Due to their low solubility in common organic solvents,
the isomers could not be separated by chromatography or crystalli-
zation. M.p. (isomeric mixture): 352–355 °C [ref.[25] m.p. (7-isomer)
1139, 712, 671 cm–1. The analytical data correspond to those re-
ported in the literature.[26]
3-Methyl-2-phenyl-1H-quinolin-4-one (6h): Aminonitrile 4h (22 mg,
0.073 mmol) was dissolved in diphenyl ether (1.5 mL) and treated
as described for the synthesis of 6a, yielding the title product as a
colorless solid (15 mg, 0.063 mmol, 86%). M.p. 287–290 °C (ref.[29]
287–290 °C). 1H NMR (400 MHz, CD3OD): δ = 8.30 (dd, 3J =
4
3
3
8.3 Hz, J = 0.9 Hz, 1 H, H5), 7.66 (dd, J = 8.3 Hz, J = 6.8 Hz,
1
361–362 °C). H NMR (400 MHz, [D6]DMSO, HMBC, HSQC): δ
4J = 1.5 Hz, 1 H, H6), 7.60 (m, 1 H, H8), 7.58–7.52 (m, 5 H,
3
= 11.73 (s, 1 H, -NHA), 8.09 (d, J = 8.6 Hz, 1 H, H5A), 7.85 (m,
3
3
4
H2Ј,3Ј,4Ј,5Ј,6Ј), 7.39 (dd, J = 8.3 Hz, J = 6.8 Hz, J = 1.2 Hz, 1
H, H7), 2.04 (s, 3 H, -CH3) ppm. 13C NMR (100 MHz, CD3OD):
δ = 161.8 (C4), 153.4 (C2), 141.2 (C8a), 136.5 (C1Ј), 133.1 (C6),
130.9 (C4Ј), 130.1 (C2Ј,6Ј), 130.0 (C3Ј,5Ј), 126.3 (C5), 124.9 (C7),
124.6 (C4a), 119.4 (C8), 117.2 (C3), 12.7 (-CH3) ppm. MS (ESI):
m/z (%) = 250.1 (5) [M + Na]+, 236.1 (100) [M + H]+. HRMS
4 H, H2ЈA,6ЈA, overlap of signals with H2ЈB,6ЈB), 7.80 (d, 4J =
3
4
1.9 Hz, 1 H, H8A), 7.70 (dd, J = 8.4 Hz, J = 1.0 Hz, 1 H, H8B),
7.61–757 (m,
7
H, H3ЈA,4ЈA,5ЈA, overlap of signals with
3
4
H3ЈB,4ЈB,5ЈB,H7B), 7.36 (dd, J = 8.6 Hz, J = 2.0 Hz, 1 H, H6A),
7.27 (dd, J = 7.7 Hz, J = 1.0 Hz, 1 H, H6B), 6.39 (s, 1 H, H3A),
6.32 (s, 1 H, H3B) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
176.6 (C4A), 151.0 (C2A), 141.9 (C8aA), 136.7 (C7A), 134.5 (C1ЈA),
131.9 (C7B), 130.5 (4ЈA), 128.9 (C3ЈA,5ЈA), 127.9 (C3ЈB,5ЈB), 127.8
(C2ЈA,6ЈA), 126.6 (C2ЈB,6ЈB), 127.3 (C5A), 126.3 (C4aA), 126.1
(C6B), 123.6 (C6A), 118.8 (C8B), 118.4 (C8A), 109.7 (C3B), 108.1
(C3A) ppm. The resonances of C1ЈB, C4ЈB, C4B, C4aB and C8aB
could not be detected due to the low solubility of 6e in DMSO.
MS (ESI): m/z (%) = 256.1 (100) [M + H]+. HRMS (ESI): calcd.
3
4
(ESI): calcd. for [M]+ 235.0997; found 235.1001. IR (ATR): ν =
˜
1627, 1573, 1547, 1427, 1008, 760, 696 cm–1. The analytical data
correspond to those reported in the literature.[29]
3-Ethyl-2-phenyl-1H-quinolin-4-one (6i): Aminonitrile 4i (78 mg,
0.24 mmol) was dissolved in diphenyl ether (2 mL), and the mixture
was heated to 250 °C for 15 min. The product was precipitated with
n-hexane (1 mL), centrifuged, decanted, and washed four times
with n-hexane (1 mL) to remove the remaining diphenyl ether. The
title compound was obtained as a light brown solid (46 mg,
0.19 mmol, 75%). M.p. 230–232 °C. 1H NMR (400 MHz, [D6]
DMSO): δ = 11.58 (s, 1 H, -NH), 8.17–8.15 (m, 1 H, H7), 7.66–
for [M + H]+ 256.0524; found 256.0529. IR (ATR): ν = 1632, 1581,
˜
1547, 1495, 1076, 819, 762, 687 cm–1. The analytical data corre-
spond to those reported in the literature.[25]
2-(4-Methoxyphenyl)-1H-quinolin-4-one (6f): Aminonitrile 4f 7.61 (m, 5 H, H2Ј,3Ј,4Ј,5Ј,6Ј), 7.60–7.58 (m, 2 H, H5,6), 7.28 (dt,
(37 mg, 0.11 mmol) was dissolved in diphenyl ether (1.5 mL) and
heated for 15 min to 250 °C. The product was precipitated with n-
hexane (1 mL) and separated by centrifugation and decantation
from diphenyl ether. The remainder was washed four times with n-
3J = 8.1 Hz, 4J = 6.0 Hz, 5J = 2.0 Hz, 1 H, H8), 2.32 (q, 3J =
15.4 Hz, 2 H, -CH2CH3), 0.95 (t, 3J = 7.36 Hz, 3 H, -CH2CH3)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 176.5 (C4), 147.9
(C2), 139.6 (C8a), 135.1 (C1Ј), 129.2 (C4Ј), 129.1 (C6), 128.5 (C3Ј),
124.88 (C7), 122.5 (C8), 120.5 (C3), 118.3 (C5), 117.9 (C4a), 19.09
hexane (1 mL) to yield quinolone 6f as a colorless solid (26 mg,
1
0.10 mmol, 91%). M.p. 294–295 °C (ref.[24] 294–296 °C). H NMR (-CH2CH3), 13.95 (-CH2CH3) ppm. MS (FAB): m/z (%) = 251.2
(400 MHz, [D6]DMSO): δ = 11.59 (s, 1 H, -NH), 8.08 (d, 3J =
8.0 Hz, 1 H, H5), 7.81 (AAЈ part of the AAЈBBЈ spin system, 2 H,
(20) [M + H]+, 250.2 (100) [M]+, 234.2 (7) [M – CH3]+. HRMS
(FAB): calcd. for [M]+ 249.1154; found 249.1154. IR (ATR): ν =
˜
3
3
H3Ј,H5Ј) 7.76 (d, J = 8.2 Hz, 1 H, H8), 7.65 (t, J = 6.9 Hz, 1 H, 2957, 1625, 1542, 1492, 758, 697, 688 cm–1. The analytical data
3
H6), 7.31 (t, J = 7.4 Hz, 1 H, H7), 7.13 (BBЈ part of the AAЈBBЈ
spin system, 2 H, H2Ј,H6Ј), 6.32 (s, 1 H, H3), 3.85 (s, 3 H, -OCH3)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 161.0 (C4Ј), 149.8
(C2), 140.9 (C8a), 131.4 (C6), 128.6 (C3Ј,5Ј), 126.5 (C1Ј), 124.9
(C4a), 124.6 (C5), 123.0 (C7), 119.2 (C8), 114.3 (C2Ј,6Ј), 106.4
(C3), 55.4 (-OCH3) ppm. The resonance of C4 could not be de-
tected. MS (ESI): m/z (%) = 252.1 (100) [M + H]+. HRMS (ESI):
correspond to those reported in the literature.[30]
2,3-Diphenyl-1H-quinolin-4-one (6j): Aminonitrile 4j (16 mg,
0.043 mmol) was dissolved in diphenyl ether (1.5 mL) and heated
to 250 °C. Workup was performed as described for the synthesis of
6a, furnishing quinolone 6j as a colorless solid (10 mg, 0.035 mmol,
1
81%). M.p. 342–345 °C (ref.[31] 342–345 °C). H NMR (400 MHz,
CD3OD, COSY): δ = 8.33 (d, 3J = 8.2 Hz, 1 H, H5), 7.75–7.67 (m,
2 H, H6,7), 7.44 (dt, 3J = 7.1 Hz, 1 H, H8), 7.37–7.08 (m, 5 H,
H2ЈЈ,3ЈЈ,4ЈЈ,5ЈЈ,6ЈЈ), 7.22–7.13 (m, 5 H, H2Ј,3Ј,4Ј,5Ј,6Ј) ppm. 13C
NMR (100 MHz, CD3OD, HSQC, HMBC): δ = 176.9 (C4), 152.4
(C2), 150.6 (C3), 141.7 (C8a), 136.9 (C1ЈЈ), 134.2 (C4a), 133.5
(C1Ј), 133.0 (C7), 130.7 (C5Ј,3Ј), 130.3 (C4ЈЈ), 129.3 (C5ЈЈ,3ЈЈ),
127.8 (C2ЈЈ,6ЈЈ), 128.8 (C2Ј,6Ј), 127.7 (C4Ј), 126.7 (C5), 125.2 (C8),
119.3 (C6) ppm. MS (ESI): m/z (%) = 320.1 (2) [M + Na]+, 298.1
(100) [M + H]+. HRMS (ESI): calcd. for [M]+ 297.1154; found
calcd. for [M + H]+ 251.0946; found 251.0949. IR (ATR): ν = 1631,
˜
1550, 1248, 1030, 818, 676 cm–1. The analytical data correspond to
those reported in the literature.[28]
2-(2-Chlorophenyl)-1H-quinolin-4-one (6g): A solution of aminoni-
trile 4g (51 mg, 0.16 mmol) in diphenyl ether (2 mL) was heated for
20 min to 250 °C. The addition of n-hexane (1 mL) yielded a
brownish solid, which was centrifuged, decanted, and washed five
times with n-hexane (1 mL). For further purification, the crude
product was passed over a short pad of silica (CH2Cl2). Elution
with methanol gave the title compound as a brownish oil (33 mg,
297.1155. IR (ATR): ν = 1621, 1577, 1508, 1485, 756, 698 cm–1.
˜
The analytical data correspond to those reported in the litera-
ture.[31]
3
0.13 mmol, 81%). 1H NMR (400 MHz, CD3OD): δ = 8.25 (d, J
3
= 8.3 Hz, 1 H, H5), 7.72–7.68 (m, 1 H, H7), 7.63 (d, J = 8.3 Hz,
Ethyl 2-Phenylquinoline-3-carboxylate (7):[32] DMF (22 mg,
0.30 mmol, 23 µL) was cooled to 0 °C, then POCl3 (46 mg,
1 H, H6), 7.62–7.40 (m, 5 H, H8, 3Ј, 4Ј, 5Ј, 6Ј), 6.30 (s, 1 H, H3)
ppm. 13C NMR (100 MHz, CD3OD): δ = 180.4 (C4), 151.5 (C2Ј), 0.30 mmol, 27 µL) was added. The yellow mixture was stirred for
141.7 (C8a), 133.9 (C7), 133.8 (C3Ј), 133.6 (C2), 132.8 (5Ј), 132.0 30 min at room temperature. Subsequently, a solution of 5a (67 mg,
(4Ј), 131.3 (C1Ј), 128.6 (C6Ј), 126.1 (C5), 125.8 (C4a), 125.6 (C8), 0.25 mmol) in chloroform (800 µL) was added, and the mixture was
119.5 (C6), 111.1 (C3) ppm. MS (ESI): m/z (%) = 256.1 (100) [M
stirred for 20 h at 80 °C. The reaction was quenched by addition
saturated aqueous NaHCO3 solution (1 mL) and extracted with
ethyl acetate. The organic layer was washed with a saturated aque-
+ H]+. HRMS (ESI): calcd. for [M + H]+ 256.0524; found
256.0527. IR (film): ν = 3062, 2796, 1634, 1569, 1544, 1411, 1355,
˜
Eur. J. Org. Chem. 2010, 5841–5849
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5847

A. Romek, T. Opatz
FULL PAPER
ous NaHCO3 solution and concentrated in vacuo. Purification was
carried out by flash chromatography (cyclohexane/ethyl acetate,
9:1), yielding the title compound as a slightly yellowish oil (56 mg,
20 mmol, 81%). Rf = 0.16 (cyclohexane/ethyl acetate, 1:1). 1H
NMR (400 MHz, CDCl3): δ = 8.68 (s, 1 H, H4), 8.27–8.25 (m, 1
Acknowledgments
This work was supported by the Deutsche Forschungsgemein-
schaft.
3
3
H, H5), 7.94 (d, J = 8.1 Hz, 1 H, H8), 7.84 (t, J = 7.7 Hz, 1 H,
H7), 7.65–7.61 (m, 3 H, H6, H2Ј,6Ј), 7.49–7.45 (m, 3 H, H3Ј,4Ј,5Ј),
[1]
a) A. A. Boteva, O. P. Krasnykh, Chemistry of Heterocyclic
Compounds, Springer, New York, 2009, vol. 45, pp. 757–785;
b) D. C. Hooper, E. Rubinstein (Eds.), Quinolone Antimicrobial
Agents, ASM Press, Washington, 2003; c) L. A. Mitscher,
Chem. Rev. 2005, 105, 559–592.
3
4.20 (q, 3J = 7.1 Hz, 2 H, -OCH2CH3), 1.08 (t, J = 7.1 Hz, 3 H, -
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.4 (CO),
157.5 (C2), 147.2 (C8a), 139.6 (C4), 132.1 (C7), 129.2 (C3), 129.0
(C6), 128.9 (C2Ј,6Ј), 128.9 (C5), 128.4 (C8), 128.4 (C3Ј,5Ј), 127.7
(C4Ј), 126.0 (C4a), 61.6 (-OCH2CH3), 13.7 (-OCH2CH3) ppm. MS
(ESI): m/z (%) = 278.1 (100) [M + H]+. HRMS (ESI): calcd. for
[2]
[3]
R. Wise, J. M. Andrews, L. J. Edwards, Antimicrob. Agents
Chemother. 1983, 23, 559–564.
I. Hayakawa, S. Atarashi, S. Yokohama, M. Imamura, K. Sak-
ano, M. Furukawa, Antimicrob. Agents Chemother. 1986, 29,
163–164.
[M + H]+ 278.1176; found 278.1184. IR (film): ν = 3059, 2981,
˜
1722, 1619, 1555, 1445, 1200, 1019, 803, 771 cm–1. The analytical
data correspond to those reported in the literature.[33]
[4]
a) S. C. Kuo, H. Z. Lee, J. P. Juang, Y. T. Lin, T. S. Wu, J. J.
Chang, D. Lednicer, K. D. Paull, C. M. Lin, J. Med. Chem.
1993, 36, 1146–1156; b) L. Li, H.-K. Wang, S.-C. Kuo, T.-S.
Wu, D. Lednicer, C. M. Lin, E. Hamel, K.-H. Lee, J. Med.
Chem. 1994, 37, 1126–1135; c) Y. Xia, Z.-Y. Yang, P. Xia, T.
Hackl, E. Hamel, A. Mauger, J.-H. Wu, K.-H. Lee, J. Med.
Chem. 2001, 44, 3932–3936; d) Y.-C. Chen, P.-H. Lu, S.-L. Pan,
C.-M. Teng, S.-C. Kuo, T.-P. Lin, Y.-F. Ho, Y.-C. Huang, J.-H.
Guh, Biochem. Pharmacol. 2007, 74, 10–19; e) S.-W. Wang, S.-
L. Pan, Y.-C. Huang, J.-H. Guh, P.-C. Chiang, D.-Y. Huang,
S.-C. Kuo, K.-H. Lee, C.-M. Teng, Mol. Cancer Ther. 2008, 7,
350–360.
2-Phenyl-4-trifluoromethylsulfonyloxyquinoline (8): Quinolone 6a
(70 mg, 0.32 mmol) and DMAP (23 mg, 0.19 mmol, 0.50 equiv.)
were coevaporated with pyridine (0.2 mL) to remove trace amounts
of water, and the residue was dissolved in pyridine (5 mL). The
mixture was cooled to 0 °C, then trifluoromethanesulfonic acid an-
hydride (108 mg, 0.380 mmol, 64.2 µL, 1.2 equiv.) was added. The
mixture was allowed to stir for 6 h at room temperature. Pyridine
was removed in vacuo, and the remainder was purified by filtration
through a short pad of silica (dichloromethane) to furnish the title
1
compound as a yellowish oil (89 mg, 0.25 mmol, 79%). H NMR
3
3
[5]
(400 MHz, CDCl3): δ = 8.25 (d, J = 8.5 Hz, 1 H, H5), 8.15 (d, J
a) R. Camps, Ber. Dtsch. Chem. Ges. 1899, 32, 3228–3234; b)
R. Camps, Arch. Pharm. 1899, 237, 659–691; c) R. Camps,
Arch. Pharm. 1901, 591–610; d) R. C. Fuson, D. M. Burness,
J. Am. Chem. Soc. 1946, 68, 1270–1272; e) R. H. Reitsema,
Chem. Rev. 1948, 43, 43–68; f) Z. Sui, V. N. Nguyen, J. Altom,
J. Fernandez, J. J. Hilliard, J. I. Bernstein, J. F. Barrett, K. A.
Ohemeng, Eur. J. Med. Chem. 1999, 34, 381–387; g) R. D.
Larsen, Science of Synthesis, Thieme, 2005, vol. 15, p. 551–660;
h) D. Ding, X. Li, X. Wang, Y. Du, J. Shen, Tetrahedron Lett.
2006, 47, 6997–6999; i) C. P. Jones, K. W. Anderson, S. L.
Buchwald, J. Org. Chem. 2007, 72, 7968–7973; j) D. Zewge, C.-
Y. Chen, C. Deer, P. G. Dormer, D. L. Hughes, J. Org. Chem.
2007, 72, 4276–4279; k) J. Huang, Y. Chen, A. O. King, M.
Dilmeghani, R. D. Larsen, M. M. Faul, Org. Lett. 2008, 10,
2609–2612; l) T. Zhao, B. Xu, Org. Lett. 2010, 12, 212–215.
a) M. Conrad, L. Limpach, Ber. Dtsch. Chem. Ges. 1887, 20,
523–533; b) M. Conrad, L. Limpach, Ber. Dtsch. Chem. Ges.
1887, 20, 944–959; c) M. Conrad, L. Limpach, Ber. Dtsch.
Chem. Ges. 1888, 21, 521–522; d) M. Conrad, L. Limpach, Ber.
Dtsch. Chem. Ges. 1891, 24, 2990–2992; e) R. G. Gould Jr.,
W. A. Jacobs, J. Am. Chem. Soc. 1939, 61, 2890–2895; f) N. D.
Heindel, I. S. Bechara, P. D. Kennewell, J. Molnar, C. J. Ohn-
macht, S. M. Lemke, T. F. Lemke, J. Med. Chem. 1968, 11,
1218–1221; g) B. Chen, X. Huang, J. Wang, Synthesis 1987,
482–483; h) K. Grohe, The Chemistry of the Quinolones: Meth-
ods of Synthesizing the Quinolone Ring System, Springer, Hei-
delberg, 1998, vol. 127; i) V. Milata, R. M. Claramunt, J. El-
guero, P. Zalupsky, Targets Heterocycl. Syst. 2000, 4, 167–203;
j) A. S. Wagman, M. P. Wentland, Quinolone Antibacterial
Agents, Elsevier, Amsterdam, 2006, vol. 7.
3
= 8.2 Hz, 2 H, H2Ј,6Ј), 8.07 (d, J = 8.3 Hz, 1 H, H8), 7.86–7.83
3
(m, 2 H, H3, H7), 7.68 (t, J = 7.6 Hz, 1 H, H6), 7.58–7.50 (m, 3
H, H3Ј,4Ј,5Ј) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4 (C4),
153.7 (C2), 150.5 (8a), 138.4 (C1), 131.4 (C5), 130.5 (C7), 130.2
(C4Ј), 129.3 (C3Ј,5Ј), 128.6 (C6), 127.7 (C2Ј,6Ј), 120.7 (C8), 120.3
1
(C4a), 118.7 (q, JC,F = 320 Hz, CF3), 109.9 (C3) ppm. MS (ESI):
m/z (%) = 354.0 (100) [M + H]+. HRMS (ESI): calcd. for [M]+
353.0333; found 353.0337. IR (film): ν = 2957, 1644, 1606, 1428,
˜
1293, 1221, 1140, 1029 cm–1.
2,4-Diphenylquinoline (9):[34] Triflate 8 (88 mg, 0.25 mmol), phen-
ylboronic acid (46 mg, 0.38 mmol, 1.5 equiv.), and triethylamine
(50 mg, 0.50 mmol, 67 µL, 2 equiv.) were dissolved in DMF (5 mL),
then argon was bubbled into the solution. Tetrakis(triphenylphos-
phane)palladium(0) (9 mg, 3 mol-%) was added, and the reaction
mixture was heated at reflux for 4 h. For workup, brine (5 mL) was
added, and the mixture was extracted with dichloromethane
(5 mL). The organic layer was separated and washed with brine.
Dichloromethane was removed in vacuo, and the crude product
was purified by flash chromatography (dichloromethane), yielding
the title compound as a colorless oil (50 mg, 0.18 mmol, 72%). Rf
[6]
1
= 0.67 (dichloromethane). H NMR (400 MHz, CDCl3, COSY): δ
= 8.28 (d, 3J = 8.4 Hz, 1 H, H8), 8.21–8.18 (m, 2 H, H2Ј,6Ј), 7.92–
3
3
7.89 (m, 1 H, H5), 7.82 (s, 1 H, H3), 7.73 (dd, J = 8.4 Hz, J =
4
7.0 Hz, J = 1.3 Hz, 1 H, H7), 7.57–7.44 (m, 9 H, H6,3Ј,4Ј,5Ј,2ЈЈ,
3ЈЈ,4ЈЈ,5ЈЈ,6ЈЈ) ppm. 13C NMR (100 MHz, CDCl3, HSQC, HMBC):
δ = 156.9 (C2), 149.2 (C4), 148.8 (C8), 139.5 (C1Ј), 138.4 (C1ЈЈ),
136.5 (C8a), 130.0 (C7), 129.6 (C2ЈЈ,6ЈЈ), 129.5 (C4Ј), 129.4 (C6),
128.9 (C3Ј,5Ј), 128.6 (C3ЈЈ,5ЈЈ), 128.4 (C4ЈЈ), 127.6 (C2Ј,6Ј), 126.7
(C5), 125.8 (C5b), 125.7 (C4a), 119.4 (C3) ppm. MS (ESI): m/z (%)
= 282.1 (100) [M + H]+. HRMS (ESI): calcd. for [M]+ 281.1204;
[7]
[8]
[9]
a) A. Combes, Bull. Soc. Chim. Fr. 1888, 49, 89–92; b) E. Rob-
erts, E. J. Turner, Chem. Soc. 1927, 1832–1857.
a) T. Opatz, Synthesis 2009, 1941–1959; b) N. Meyer, T. Opatz,
Synlett 2003, 1427–1430.
a) C. Kison, N. Meyer, T. Opatz, Angew. Chem. Int. Ed. 2005,
44, 5662–5664; b) T. Opatz, D. Ferenc, Org. Lett. 2006, 8,
4473–4475; c) C. Kison, T. Opatz, Eur. J. Org. Chem. 2008,
2740–2745; d) C. Kison, T. Opatz, Chem. Eur. J. 2009, 15, 843–
845.
found 281.1206. IR (film): ν = 3059, 2923, 1633, 1574, 1508, 1406,
˜
731, 669 cm–1. The analytical data correspond to those reported in
the literature.[35]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra of all compounds.
[10]
F. J. McEvoy, J. D. Albright, J. Org. Chem. 1979, 44, 4597–
4603.
5848
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5841–5849

Polysubstituted 4-Quinolones from Deprotonated α-Aminonitriles
[11]
[12]
[13]
[23] A. Zhang, C. Csutoras, R. Zong, J. L. Neumeyer, Org. Lett.
2005, 7, 3239–3242.
J.-C. Brouet, S. Gu, N. P. Peet, J. D. Williams, Synth. Commun.
2009, 39, 1563–1569.
A. Zhang, C. Csutoras, R. Zong, J. L. Neumeyer, Org. Lett.
2005, 7, 3239–3242.
a) D. R. Adams, J. N. Dominguez, J. A. Perez, Tetrahedron
Lett. 1983, 24, 517–18; b) M. Anzini, A. Cappelli, S. Vomero,
G. Giorgi, T. Langer, G. Bruni, R. Romeo, A. S. Basile, J. Med.
Chem. 1996, 39, 4275–4284.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483; b)
L. Feliu, W. Ajana, M. Alvarez, J. A. Joule, Tetrahedron 1997,
53, 4511–4520.
[24] D. Ding, X. Li, X. Wang, Y. Du, J. Shen, Tetrahedron Lett.
2006, 47, 6997–6999.
[25] See ref.[4a]
[26] J. Huang, Y. Chen, A. O. King, M. Dilmeghani, R. D. Larsen,
M. M. Faul, Org. Lett. 2008, 10, 2609–2612.
[27] S. Sato, T. Watanabe, H. Kumagai, N. Kitamura, S. Matsuba,
T. Kumazawa, J.-I. Onodera, M. Suzuki, J. Heterocycl. Chem.
1999, 36, 1189–1193.
[28] S. Torii, H. Okumoto, L. H. Xu, Tetrahedron Lett. 1991, 32,
237–240.
[14]
[15]
[16]
B. C. Ranu, S. S. Dey, A. Hajra, Tetrahedron 2002, 58, 2529–
2532.
[29] F.-T. Luo, V. K. Ravi, C. Xue, Tetrahedron 2006, 62, 9365–9372.
[30] C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284.
G. Barnikow, A. Hagen, V. Hagen, E. Goeres, D. Richter, K. [31] M. J. Mphahlele, T. M. El-Gogary, J. Chem. Res. 2008, 227–
Fichtner, Pharmazie 1983, 38, 449–452.
231.
[17] B. B. Corson, R. A. Dodge, S. A. Harris, J. S. Yeaw, Org. Synth.
1926, 6, 58.
[32] D. R. Adams, J. N. Dominguez, J. A. Perez, Tetrahedron Lett.
1983, 24, 517–518.
[33] D. Lloyd, J. M. F. Gagan, J. Chem. Soc. C 1970, 2488–2492.
[34] K. Kikuchi, K. Tagami, S. Hibi, H. Yoshimura, N. Tokuhara,
K. Tai, T. Hida, T. Yamauchi, M. Nagai, Bioorg. Med. Chem.
Lett. 2001, 11, 1215–1218.
[35] A. G. Osborne, M. T. Ahmet, J. R. Miller, J. F. Warmsley, Spec-
trochim. Acta Part A 1995, 51A, 237–246.
Received: June 15, 2010
[18] W. E. McEwen, A. V. Grossi, R. J. MacDonald, A. P. Sta-
megna, J. Org. Chem. 1980, 45, 1301–1308.
[19] S. S. Naim, S. Sharma, Synthesis 1992, 664–666.
[20] N. Meyer, F. Werner, T. Opatz, Synthesis 2005, 945–956.
[21] D. Seebach, A. K. Beck, B. Schmidt, Y. M. Wang, Tetrahedron
1994, 50, 4363–4384.
[22] H. E. Gottlieb, V. A. Kotlyar, J. Nudelman, J. Org. Chem. 1997,
62, 7512–7515.
Published Online: September 1, 2010
Eur. J. Org. Chem. 2010, 5841–5849
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5849