W. Stadlbauer et al.
FULL PAPER
(90%). The mixture was separated by dry flash column chromatog-
raphy (Merck Silica gel 60 H, 5–40 µm).[18] Toluene as eluent af-
forded O-alkylated quinoline 12b (470 mg, 15 % yield) as light-
quinolinylacetic acid 14 (288 mg, 1.0 mmol) in dry tetrahydrofuran
(20 mL) at 0 °C. Then N,N-diisopropylcarbodiimide (125 mg,
1.0 mmol) was added at 0–5 °C dropwise whilst stirring, which
formed a yellowish-white precipitate; the mixture was stirred at 0–
green prisms. M.p. 158–159 °C (ethanol). IR (KBr): ν = 3480–3420
˜
(br., w), 3000–2930 (br., w), 2227 (m), 1753 (s), 1655 (w), 1621 (m), 5 °C for about 15 h, and the solvent was removed under reduced
1
1607 (m), 1511 (s) cm–1. H NMR (360 MHz, CDCl3): δ = 1.27 (t, pressure. The obtained solid was filtered by suction and washed
J = 7.1 Hz, 3 H, ethyl-CH3), 4.02 and 4.04 (2 s, 2ϫ3 H, 6- and 7-
OMe), 4.27 (q, J = 7.1 Hz, 2 H, ethyl-CH2), 5.07 (s, 2 H, acetate-
CH2), 7.02 (s, 1 H, 3-H), 7.14 (s, 1 H, 8-H), 8.26 (s, 1 H, 5-H) ppm.
MS: m/z (%) = 317 (10) [M + 1], 316 (100) [M]. C16H16N2O5
(316.32): calcd. C 60.76, H 5.10, N 8.86; found C 61.11, H 5.24, N
8.51.
with dry tetrahydrofuran. The solid was then stirred in dry ethanol
(50 mL) at 20 °C for 30 min to remove N,N-diisopropylurea formed
during the reaction. Suction filtration afforded 288 mg (59% yield)
of pale-yellow prisms. M.p. 232–233 °C (ethanol). IR (KBr): ν =
˜
3300–3550 (br., s), 2909 (m), 2223 (m), 1809 (w), 1783 (m), 1745 (s),
1660 (sh), 1646 (m), 1621 (m), 1561 (m) cm–1. 1H NMR (500 MHz,
CDCl3): δ = 2.87 (s, 4 H, 2 succinimide-CH2), 3.97 and 4.14 (2 s,
2ϫ3 H, 6- and 7-OMe), 5.56 (s, 2 H, acetate-CH2), 6.64 (s, 1 H,
3-H), 6.98 (s, 1 H, 8-H), 8.15 (s, 1 H, 5-H) ppm. UV (DMSO): λ
= 398, 385 nm. UV (water): λ = 380 nm. MS: m/z (%) = 386 (5)
[M + 1], 385 (42) [M], 288 (17), 270 (100). C18H15N3O7 (385.34):
calcd. C 56.11, H 3.92, N 10.90; found C 56.34, H 3.89, N 11.29.
6,7-Dimethoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile
(13a): The reaction was performed as described for O-methylated
quinoline 12a: dry flash column chromatography[18] of the mixture
of quinolines 12a/13a with toluene/acetone (9:1) as the eluent gave
N-methylated quinolone 13a (1.44 g, 60 % yield) as pale-yellow
prisms. M.p. 260–261 °C (ethanol). IR (KBr): ν = 3500–3350 (br.,
˜
N-[(4-Cyano-6,7-dimethoxy-2-oxo-1,2-dihydroquinolin-1-yl)acetyl-
amino]-3-phenylpropionic Acid (17a): To a solution of (, )-phenyl-
alanine (16a; 19 mg, 0.1 mmol) in 90% aqueous DMSO (1.5 mL)
was added a solution of OSu ester 15 (38 mg, 0.1 mmol) in 90%
aqueous DMSO (1.5 mL) dropwise at 20 °C. Then, aqueous pH 7
buffer solution (Merck 9887, 0.75 mL) was added. The mixture was
stirred for 14 h at 20 °C, poured into water (25 mL), and then acidi-
fied with concentrated HCl to pH = 1–2. A solid separated, which
was filtered by suction and washed with an excess amount of water
to afford 29 mg (68 % yield) of dark-yellow prisms. M.p. 242–
w), 3045 (m), 2963 (m), 2919 (w), 2226 (m), 1632 (s), 1592 (w),
1567 (w), 1524 (m) cm–1. 1H NMR (360 MHz, CDCl3): δ = 3.77
and 3.96 (2 s, 2ϫ3 H, 6- and 7-OMe), 4.06 (s, 3 H, NMe), 6.77 (s,
1 H, 3-H), 6.97 (s, 1 H, 8-H), 8.09 (s, 1 H, 5-H) ppm. UV (DMSO):
λ (ε, –1 cm–1) = 390 (12400) nm. Fluorescence data: see Table 1.
MS: m/z (%) = 245 (23) [M + 1], 244 (100) [M]. C13H12N2O3
(244.25): calcd. C 63.93, H 4.95, N 11.47; found C 63.68, H 5.23,
N 11.71.
Ethyl (4-Cyano-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-4-yl)ace-
tate (13b): The reaction was performed as described for O-alkylated
quinoline 12b: Dry flash column chromatography[18] of the mixture
of quinolines 12b/13b with toluene/acetone (9:1) as eluent afforded
N-alkylated quinolone 13b (2.37 g, 75% yield) as yellow prisms.
243 °C (acetone). IR (KBr): ν = 3550–3350 (br., w), 3295 (m), 2227
˜
(m), 1710 (m), 1654 (s), 1633 (s), 1562 (m), 1549 (w) cm–1. 1H NMR
(500 MHz, [D6]DMSO): δ = 2.90 and 3.05 (2 m, 2 H, PhCH2), 3.78
and 3.82 (2 s, 2ϫ3 H, 6- and 7-OMe), 4.42–4.44 (m, 1 H, N-CH),
4.85 (d, J = 16.4 Hz, 1 H, 1/2 acetate-CH2), 5.12 (d, J = 16.4 Hz,
1 H, 1/2 acetate-CH2), 6.60 (s, 1 H, 3-H), 7.21 (m, 5 H, PhH), 7.33
(s, 1 H, 8-H), 8.60 (s, 1 H, 5-H), 8.69 (d, J = 12.0 Hz, 1 H, NH)
ppm. UV (DMSO): λ (ε, –1 cm–1) = 385 (13300) nm. Fluorescence
(H2O): λ (ΦF) = 433 (0.73) nm. Fluorescence (DMSO): λ (ΦF) =
436 (0.60) nm. C23H21N3O6 (435.44): calcd. C 63.44, H 4.86, N
9.65; found C 63.12, H 4.51, N 10.03.
M.p. 220–221 °C (ethanol). IR (KBr): ν = 3480–3400 (br., w), 2922
˜
(m), 2963 (s), 2226 (s), 1732 (s), 1657 (s), 1625 (m), 1567 (w), 1560
1
(m), 1536 (w) cm–1. H NMR (360 MHz, CDCl3): δ = 1.28 (t, J =
7.1 Hz, 3 H, ethyl-CH3), 3.96 and 3.99 (2 s, 2ϫ3 H, 6- and 7-
OMe), 4.26 (q, J = 7.1 Hz, 2 H, ethyl-CH2), 5.11 (s, 2 H, acetate-
CH2), 6.53 (s, 1 H, 3-H), 6.99 (s, 1 H, 8-H), 8.14 (s, 1 H, 5-H)
ppm. UV (DMSO): λ (ε, –1 cm–1) = 385 (10400) nm. Fluorescence
(H2O): λ (ΦF) = 435 (0.53) nm. Fluorescence (DMSO): λ (ΦF) =
436 (0.46) nm. MS: m/z (%) = 317 (10) [M + 1], 316 (100) [M], 270
(47) [M – 46]. C16H16N2O5 (316.32): calcd. C 60.76, H 5.10, N 8.86;
found C 60.97, H 5.02, N 8.63.
(2-{2-[2-(4-Cyano-6,7-dimethoxy-2-oxo-1,2-dihydroquinolin-1-yl)-
acetylamino]acetylamino}acetylamino)acetic Acid (17b): Glycyl-gly-
cyl-glycine (16b; 20 mg, 0.1 mmol) was brought to reaction and
worked up as described for labeled phenylalanine 17a to afford
25 mg (55% yield) of dark-yellow prisms. M.p. 238–239 °C (ace-
(4-Cyano-6,7-dimethoxy-2-oxo-1,2-dihydroquinolin-1-yl)acetic Acid
(14): A solution of quinolinylacetate 13b (316 mg, 1.0 mmol) in eth-
anol (20 mL) and aqueous NaOH (1 , 2 mL) was heated under
reflux for 7 h. Ethanol was then removed under reduced pressure,
and the residue was dissolved in water (10 mL) under cooling. The
mixture was acidified with concentrated HCl to pH = 1–2, and the
resulting precipitate was filtered by suction and washed with water,
which afforded 232 mg (80% yield) as yellow prisms. M.p. 281–
tone). IR (KBr): ν = 3354 (s), 3302 (s), 3071 (m), 3047 (m), 2948
˜
(m), 2922 (m), 2224 (m), 1734 (m), 1639 (s), 1633 (s), 1566 (s), 1530
(w) cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 3.67 (d, J =
5.04 Hz, 2 H, glycyl-CH2), 3.72 (d, J = 5.76 Hz, 2 H, glycyl-CH2),
3.79 (d, J = 5.76 Hz, 2 H, glycyl-CH2), 3.81 and 3.92 (2 s, 2ϫ3 H,
6- and 7-OMe), 5.06 (s, 2 H, acetate-CH2), 6.83 (s, 1 H, 3-H), 7.34
(s, 1 H, 8-H), 8.08 (t, J = 5.79 Hz, 1 H, NH), 8.25 (t, J = 5.79 Hz,
1 H, NH), 8.60 (s, 1 H, 5-H), 8.62 (t, J = 5.79 Hz, 1 H, NH)
ppm. UV (DMSO): λ (ε, –1 cm–1) = 385 (11600) nm. Fluorescence
(H2O): λ (ΦF) = 434 (0.56) nm. Fluorescence (DMSO): λ (ΦF) =
436 (0.46) nm. C20H21N5O8 (459.42): calcd. C 52.29, H 4.61, N
15.24; found C 51.90, H 4.48, N 15.52.
282 °C (ethyl acetate). IR (KBr): ν = 3522 (s), 3400 (m), 2229 (w),
˜
1
1736 (m), 1641 (s), 1626 (s), 1596 (w), 1566 (s), 1514 (s) cm–1. H
NMR (360 MHz, [D6]DMSO): δ = 3.82 and 3.92 (2 s, 2ϫ3 H, 6-
and 7-OMe), 5.09 (s, 2 H, acetate-CH2), 6.99 (s, 1 H, 3-H), 7.35 (s,
1 H, 8-H), 8.63 (s, 1 H, 5-H) ppm. UV (DMSO): λ (ε, –1 cm–1) =
398, 385 (9800) nm. UV (water): λ (ε, –1 cm–1) = 380 (8700) nm.
MS: m/z (%) = 289 (16) [M + 1], 288 (80) [M], 244 (28), 243 (28),
184 (100). C14H12N2O5 (288.26): calcd. C 58.33, H 4.20, N 9.72;
found C 57.95, H 4.34, N 9.38.
Acknowledgments
This research was supported by scholarships from the Austrian Ac-
ademic Exchange Service (ÖAD EZA project 894/05, for A. B. A.)
and the Central European Exchange Program for University Stud-
ies (CEEPUS network, for J. S. and H. P.).
1-{2-[(2,5-Dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-6,7-dimethoxy-2-
oxo-1,2-dihydroquinoline-4-carbonitrile (15): N-Hydroxysuccinimide
(115 mg, 1.0 mmol) was added slowly with stirring to a solution of
570
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Eur. J. Org. Chem. 2008, 563–571