Synthesis of novel halogenated 4(1H)-quinolones by thermolysis of arylaminomethylene-1,3-dioxane-4,6-diones

Article abstract of DOI:10.1055/s-0028-1083237

A variety of novel 4(1H)-quinolone derivatives were prepared by thermolysis of aminomethylene Meldrum's acid derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083237

PAPER
69
Synthesis of Novel Halogenated 4(1H)-Quinolones by Thermolysis of
Arylaminomethylene-1,3-dioxane-4,6-diones
Synthesis of
H
v
alogenated
4
e
(1
H
)-Quin
n
olones Rotzoll,a Helmut Reinke,a Christine Fischer,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 13 July 2008
substituted 4(1H)-quinolones as the ester groups present
at these positions have to be removed in several steps.
Heindel et al. reported10 and elegant approach to 4(1H)-
quinolones by nucleophilic addition of anilines to methyl
acetylenecarboxylate and subsequent cyclization. Some
drawbacks of this method are the low yields and long re-
action times in the case of electron-poor anilines. An effi-
cient approach to 4(1H)-quinolones relies on the
thermolysis of arylaminomethylene-1,3-dioxane-4,6-di-
ones available from Meldrum’s acid.11,12 This method has
been applied so far to the synthesis of nitro- and methoxy-
substituted 4(1H)-quinolones. Herein, we report what is,
to the best of our knowledge, the first application to the
synthesis of various halogenated 4(1H)-quinolones. The
products represent potentially useful synthetic building
blocks in medicinal chemistry.
Abstract: A variety of novel 4(1H)-quinolone derivatives were
prepared by thermolysis of aminomethylene Meldrum’s acid deriv-
atives.
Key words: N-heterocycles, quinolones, cyclizations
Quinolone alkaloids are widespread in nature. For exam-
ple, 4(1H)-quinolones A and B (Figure 1) occur in marine
sponges, such as Verongia aerophoba1 or Dendrilla mem-
branosa,2 in bacteria (e.g., in Pseudomonas aeruginosa)3
,
or in terrestrial plants, such as Galipea officinales.4
O
OH
O
OH
OH
N
H
CO2H
N
H
The reaction of anilines 1a–q with Meldrum’s acid (2) af-
forded arylaminomethylene-1,3-dioxane-4,6-diones 3a–q
(Table 1). Reflux of a diphenyl ether solution of the latter
afforded the novel 4(1H)-quinolones 4a–q. All reactions
proceeded in good to excellent yields. This includes a
number of chloride- and bromide-substituted 4(1H)-qui-
nolones, derived from the corresponding electron-poor
anilines, which could also be prepared in good yields. The
method is limited to the use of symmetrical or ortho-sub-
stituted anilines. The thermolysis of 3l, derived from 3-
chloroaniline, resulted in the formation of a mixture of
regioisomeric 4(1H)-quinolones.
OH
B
A
Figure 1 4(1H)-Quinolone alkaloids from Verongia aerophoba
4(1H)-Quinolones also constitute an important class of
antibiotics (Figure 2). The activity relies on the inhibition
of topoisomerase II (Gyrase-A subunit).5,6 In addition,
4(1H)-quinolones represent important intermediates in or-
ganic synthesis.7
O
O
F
CO2H
F
CO2H
The structures of all products were established by spectro-
scopic methods. The structures of 3d and 4o were inde-
pendently confirmed by X-ray crystal structure analyses
(Figure 3 and Figure 4).13 Products 3 contain an intramo-
lecular hydrogen bond N–H⋅⋅⋅O, which can be detected in
solution (low field signal in the 1H NMR spectrum) and in
the solid state (crystal structure analysis of 3d). Products
4 can exist as 4(1H)-quinolones or as tautomeric 4-hy-
droxyquinolines. All products show only one set of NMR
signals. In the solid state 4o exists in the 4(1H)-quinolone
tautomeric form with intermolecular hydrogen bonds be-
tween the NH and O4 (the hydrogen position could be elu-
cidated from the difference map and was refined freely).
N
N
N
N
HN
Et
HN
c-Pr
norfloxacin
ciprofloxacin
Figure 2 Antimicrobial 4(1H)-quinolones norfloxacin (Norfluxx®)
and ciprofloxacin (Ciprobay®)
Classic syntheses of 4(1H)-quinolones rely on the addi-
tion of (ethoxymethylene)malonates with anilines and
subsequent cyclization8 and on the addition of maleates to
o-aminobenzoates and subsequent cyclization.9 However,
these methods are not suitable for the synthesis of 2,3-un-
N-Protected 4(1H)-quinolones represent important syn-
thetic building blocks.14 The reaction of 4(1H)-quinolones
4 with methyl, ethyl, allyl, and benzyl chloroformate 5a–
d afforded the N-protected 4(1H)-quinolones 6a–h
SYNTHESIS 2009, No. 1, pp 0069–0078
Advanced online publication: 01.12.2008
0
2
.
0
1
.2
0
0
9
DOI: 10.1055/s-0028-1083237; Art ID: C04108SS
© Georg Thieme Verlag Stuttgart · New York

70
S. Rotzoll et al.
PAPER
Table 2 Synthesis of N-Protected 4(1H)-Quinolones 6a
Table 1 Synthesis of Novel 4(1H)-Quinolones
O
O
R4
R1
O
R1
O
R4
ClCO2R4
R3
R2
R2
R3
R2
R3
O
O
R3
R2
O
O
5
2
(i)
N
O
N
H
N
NH2
HC(OMe)3
reflux, 2 h
H
R1
CO2R4
R1
O
4
6a–h
1a–q
3a–q
Product 6 R1
R2
R3
R4
Yield
(%)b
R4
O
Ph2O, reflux, 1 h
R3
R2
– acetone
– CO2
a
b
c
d
e
f
H
Cl
Br
Br
F
H
Me
Me
Et
71
84
70
63
66
79
84
45
N
H
H
H
R1
H
H
4a–q
H
H
Me
Me
allyl
allyl
Bn
Products R1
3,4
R2
R3
R4
Yield (%)a Yield(%)a
of 3
78
83
75
96
69
82
73
76
78
53
72
58
68
80
45
84
75
of 4
61
75
55
67
76
90
69
72
84
83
70
73b
54
78
62
61
71
Cl
Me
H
H
Cl
Me
H
a
b
c
-(CH)4-
Ph
H
H
H
H
H
H
H
H
g
h
F
t-Bu
H
H
H
t-Bu
H
a Reaction conditions: (i) 4 (1.0 equiv), NaH (2.6 equiv), ClCO2R4
(2.6 equiv), THF, 20 °C, 48 h.
d
e
Me
H
H
Me
Me
Me
H
Me
H
H
b Isolated yields.
f
Me
Me
Cl
Me
Cl
Me
H
g
h
i
H
H
H
CF3
H
H
H
j
H
I
H
k
l
Br
H
H
H
H
Br
H
H
H
m
n
o
p
q
Br
Br
Cl
H
H
Cl
H
H
Cl
Cl
H
H
Figure 3 ORTEP plot of 3d (50% probability level)
Cl
H
Cl
Cl
Cl
H
Cl
a Isolated yields.
b Mixture of regioisomeric 5- and 7-bromoquinolone (ratio 1:1.6).
(Table 2). The structure of 6c was independently con-
firmed by X-ray crystal structure analysis (Figure 5).13
In conclusion, we have reported the synthesis of a variety
of novel protected and unprotected 4(1H)-quinolones
based on the thermolysis of aminomethylene Meldrum’s
acids.
All solvents were dried by standard methods and all reactions were
carried out under an inert atmosphere. For 1H and 13C NMR spectra
the deuterated solvents indicated were used. Mass spectrometric
data were obtained by electron ionization (EI, 70 eV), chemical ion-
ization (CI, H2O), or electrospray ionization (ESI). For preparative-
Figure 4 ORTEP plot of 4o (50% probability level)
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

PAPER
Synthesis of Halogenated 4(1H)-Quinolones
71
MS (EI, 70 eV): m/z (%) = 323 ([M]+, 26), 265 (85), 220 (57), 193
(100), 180 (63), 167 (20), 152 (23).
Anal. Calcd for C19H17NO4 (323.34): C, 70.58; H, 5.30; N, 4.33.
Found: C, 70.67; H, 5.25; N, 4.20.
5-{[(4-tert-Butylphenyl)amino]methylene}-2,2-dimethyl-1,3-di-
oxane-4,6-dione (3c)
Starting from Meldrum’s acid 2 (7.00 g, 48.60 mmol), trimethyl
orthoformate (91.5 mL, 837.80 mmol), and 4-tert-butylaniline (1c;
5.00 g, 33.50 mmol), 3c was isolated as a yellow solid (7.62 g,
75%); mp 148 °C.
IR (KBr): 3190 (br, m), 3059 (w), 2962 (m), 2870 (w), 1733 (s),
1682 (br, s), 1623 (br, s), 1579 (s), 1456 (br, s), 1272 (br, s), 1141
(m), 1003 (m), 992 cm–1 (m).
Figure 5 ORTEP plot of 6c (50% probability level)
1H NMR (250 MHz, CDCl3): d = 1.32 (s, 9 H, 3 × CH3), 1.74 (s, 6
scale chromatography, silica gel (60–200 mesh) was used. Melting
points are uncorrected.
3
H, 2 × CH3), 7.17 (d, 3J = 8.8 Hz, 2 H, Ar), 7.43 (d, J = 8.8 Hz, 2
H, Ar), 8.62 (d, 3J = 14.5 Hz, 1 H, =CH), 11.23 (br d, 3J = 14.5 Hz,
1 H, NH).
13C NMR (63 MHz, CDCl3): d = 27.0 (2 × CH3), 31.2 (3 CH3), 34.6
(CCH3), 86.8 (OCCH3), 105.1 (C), 117.7, 127.0 (CHAr), 135.2,
150.3 (C), 152.5 (=CH), 163.6, 165.7 (C=O).
MS (EI, 70 eV): m/z (%) = 303 ([M]+, 3), 245 (7), 201 (25), 186
(100), 160 (29), 144 (34), 117 (10).
Arylaminomethylene-1,3-dioxane-4,6-diones 3a–q; General
Procedure
A solution of Meldrum’s acid 2 (1.5 equiv) and trimethyl orthofor-
mate (25.0 equiv) was heated under reflux for 2 h under argon. The
solution was cooled to r.t., the appropriate aniline 1a–q (1.0 equiv)
was added and the mixture was heated under reflux for 2 h. The pre-
cipitated product was washed with MeOH (10 mL) and dried. For
products that did not precipitate, the solvent was removed in vacuo
and the residue was washed with MeOH (10 mL) and dried.
Anal. Calcd for C17H21NO4 (303.35): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.15; H, 6.84; N, 4.46.
2,2-Dimethyl-5-[(naphthalen-1-ylamino)methylene]-1,3-di-
oxane-4,6-dione (3a)
Starting from Meldrum’s acid 2 (7.30 g, 50.60 mmol), trimethyl
orthoformate (95.7 mL, 875.00 mmol), and 1-naphthylamine (1a;
5.00 g, 34.90 mmol), 3a was isolated as a yellow solid (8.11 g,
78%); mp 148 °C.
5-{[(2,5-Dimethylphenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3d)
Starting from Meldrum’s acid 2 (5.88 g, 40.80 mmol), trimethyl
orthoformate (85.6 mL, 783.80 mmol), and 2,5-dimethylaniline
(1d; 3.80 g, 31.40 mmol), 3d was isolated as a yellow solid (8.35 g,
96%); mp 163 °C.
IR (KBr): 3058 (m), 2994 (m), 2939 (m), 1724 (s), 1683 (br, s),
1634 (br, s), 1594 (br, s), 1574 (br, m), 1279 (br, s), 1205 (br, s),
1010 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.79 (s, 6 H, 2 × CH3), 7.39–7.50
(m, 2 H, Ar), 7.54–7.64 (m, 2 H, Ar), 7.77–7.99 (m, 3 H, Ar), 8.72
(d, 3J = 13.9 Hz, 1 H, =CH), 11.95 (br d, 3J = 13.9 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.1 (2 × CH3), 80.0 (OCCH3),
105.3 (C), 114.9, 120.2 (CHAr), 125.4 (C), 125.6, 127.2, 127.5,
127.6, 128.8 (CHAr), 134.1 (C), 154.4 (=CH), 163.5, 166.1 (C=O).
IR (KBr): 3162 (br, w), 3061 (m), 2985 (m), 1725 (s), 1669 (br, s),
1636 (s), 1608 (br, s), 1444 (s), 1275 (br, s), 1022 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 6 H, 2 × CH3), 2.36 (s, 6
H, 2 × CH3), 6.99 (d, 3J = 7.6 Hz, 1 H, Ar), 7.13 (s, 1 H, Ar), 7.14
(d, 3J = 7.6 Hz, 1 H, Ar), 8.64 (d, 3J = 13.9 Hz, 1 H, =CH), 11.38 (br
d, 3J = 13.9 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 16.9, 21.1 (CH3), 27.1 (2 × CH3),
87.2 (OCCH3), 105.1 (C), 117.0 (CHAr), 125.0 (C), 127.6, 131.4
(CHAr), 136.3, 137.7 (C), 152.8 (=CH), 163.7, 165.8 (C=O).
MS (EI, 70 eV): m/z (%) = 297 ([M]+, 18), 239 (55), 195 (63), 167
(100), 139 (26), 127 (20), 115 (9).
MS (EI, 70 eV): m/z (%) = 275 ([M]+, 14), 217 (49), 173 (30), 158
(100), 144 (36), 130 (33), 103 (10).
Anal. Calcd for C17H15NO4 (297.31): C, 68.68; H, 5.09; N, 4.71.;
Found: C, 68.57; H, 5.08; N, 4.52.
Anal. Calcd for C15H17NO4 (275.30): C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.33; H, 6.26; N, 5.00.
5-[(Biphenyl-2-ylamino)methylene]-2,2-dimethyl-1,3-dioxane-
4,6-dione (3b)
Starting from Meldrum’s acid 2 (4.32 g, 30.00 mmol), trimethyl
orthoformate (56.6 mL, 517.50 mmol), and 2-phenylaniline (1b;
3.50 g, 20.70 mmol), 3b was isolated as a yellow solid (5.79 g,
83%); mp 122 °C.
5-{[(3,5-Dimethylphenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3e)
Starting from Meldrum’s acid 2 (5.88 g, 40.80 mmol), trimethyl
orthoformate (85.6 mL, 783.80 mmol), and 3,5-dimethylaniline
(1e; 3.80 g, 31.40 mmol), 3e was isolated as a yellow solid (5.93 g,
69%); mp 168 °C.
IR (KBr): 3187 (br, m), 3089 (m), 2999 (m), 1730 (s), 1685 (br, s),
1631 (br, s), 1605 (br, s), 1441 (br, s), 1267 (br, s), 1118 (br, s), 1008
cm–1 (m).
IR (KBr): 3165 (br, m), 3062 (m), 2988 (m), 1722 (s), 1672 (br, s),
1633 (br, s), 1595 (br, s), 1483 (s), 1283 (br, s), 1205 (br, s), 1013
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.75 (s, 6 H, 2 × CH3), 2.34 (s, 6
H, 2 × CH3), 6.88 (s, 2 H, Ar), 6.90 (s, 1 H, Ar), 8.63 (d,
3J = 14.3 Hz, 1 H, =CH), 11.15 (br d, 3J = 14.3 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 21.3 (2 × CH3), 27.1 (2 × CH3),
86.9 (OCCH3), 105.1 (C), 115.8, 128.6 (CHAr), 137.7, 140.1 (C),
152.5 (=CH), 163.7, 165.5 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.68 (s, 6 H, 2 × CH3), 7.35–7.53
3
(m, 9 H, Ar), 8.65 (d, J = 14.2 Hz, 1 H, =CH), 11.37 (br d,
3J = 14.2 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.1 (2 × CH3), 87.5 (OCCH3),
105.0 (C), 116.1, 126.7, 128.7, 129.2, 129.2, 129.4, 131.4 (CHAr),
133.8, 135.3, 136.3 (C), 152.1 (=CH), 163.7, 165.1 (C=O).
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

72
S. Rotzoll et al.
PAPER
MS (EI, 70 eV): m/z (%) = 275 ([M]+, 37), 217 (84), 172 (39), 158
MS (EI, 70 eV): m/z (%) = 295 ([M]+, 34), 237 (100), 193 (83), 178
(100), 145 (63), 130 (49), 103 (10).
(80), 165 (66), 130 (62), 117 (25).
Anal. Calcd for C15H17NO4 (275.30): C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.29; H, 6.26; N, 4.93.
Anal. Calcd for C14H14ClNO4 (295.72): C, 56.86; H, 4.77; N, 4.74.
Found: C, 56.96; H, 4.76; N, 4.66.
2,2-Dimethyl-5-{[(2,4,5-trimethylphenyl)amino]methylene}-
1,3-dioxane-4,6-dione (3f)
Starting from Meldrum’s acid 2 (6.90 g, 47.88 mmol), trimethyl
orthoformate (90.0 mL, 824.09 mmol), and 2,4,5-trimethylaniline
(1f; 4.37 g, 32.32 mmol), 3f was isolated as a yellow solid (7.40 g,
82%); mp 175 °C.
2,2-Dimethyl-5-{([(2-(trifluoromethyl)phenyl]amino}methyl-
ene)-1,3-dioxane-4,6-dione (3i)
Starting from Meldrum’s acid 2 (6.48 g, 45.00 mmol), trimethyl
orthoformate (84.9 mL, 776.40 mmol), and 2-(trifluorometh-
yl)aniline (1i; 5.00 g, 31.10 mmol), 3i was isolated as a yellow solid
(7.64 g, 78%); mp 128 °C.
IR (ATR): 3003 (w), 2945 (w), 1721 (m), 1663 (m), 1606 (br, m),
1432 (br, m), 1264 (br, m), 1198 (br, m), 929 (m), 773 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 1.75 (s, 6 H, 2 CH3), 2.23 (s, 3 H,
CH3), 2.26 (s, 3 H, CH3), 2.32 (s, 3 H, CH3), 7.00 (s, 1 H, Ar), 7.07
(s, 1 H, Ar), 8.59 (d, 3J = 14.3 Hz, 1 H, =CH), 11.35 (br d,
3J = 14.3 Hz, 1 H, NH).
IR (KBr): 3162 (br, m), 3052 (m), 2978 (m), 1736 (s), 1678 (br, s),
1623 (s), 1590 (s), 1435 (br, s), 1270 (br, s), 1200 (br, s), 1009
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.79 (s, 6 H, 2 × CH3), 7.42–7.53
3
(m, 2 H, Ar), 7.69–7.76 (m, 2 H, Ar), 8.65 (d, J = 13.4 Hz, 1 H,
=CH), 11.74 (br d, 3J = 13.4 Hz, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 16.7, 19.2, 19.5 (CH3), 27.0 (2 ×
CH3), 86.7 (OCCH3), 105.1 (C), 117.7 (CHAr), 125.3 (C), 132.6
(CHAr), 134.1, 135.5, 136.1 (C), 152.8 (=CH), 163.8, 165.9 (C=O).
MS (EI, 70 eV): m/z (%) = 289 ([M]+, 15), 231 (33), 187 (51), 172
(100), 158 (15), 144 (23), 91 (7).
13C NMR (100 MHz, CDCl3): d = 27.2 (2 × CH3), 89.4 (OCCH3),
105.4 (C), 119.4 (CH), 121.3 (q, 1JF,C = 246 Hz, CF3), 122.0, 124.7
(C), 126.6, 127.3, 133.8 (CHAr), 136.3 (C), 153.6 (=CH), 163.2,
165.2 (C=O).
MS (EI, 70 eV): m/z (%) = 315 ([M]+, 19), 257 (100), 229 (75), 212
(65), 192 (15), 165 (29), 145 (29).
Anal. Calcd for C16H19NO4 (289.23): C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.32; H, 6.46; N, 4.76.
Anal. Calcd for C14H12F3NO4 (315.24): C, 53.34; H, 3.84; N, 4.44.
Found: C, 53.37; H, 3.84; N, 4.36.
5-{[(4-Chloro-2-methylphenyl)amino]methylene}-2,2-dimeth-
yl-1,3-dioxane-4,6-dione (3g)
Starting from Meldrum’s acid 2 (7.37 g, 51.20 mmol), trimethyl
orthoformate (96.4 mL, 882.50 mmol), and 4-chloro-2-methyl-
aniline (1g; 5.00 g, 35.30 mmol), 3g was isolated as a yellow solid
(7.59 g, 73%); mp 185 °C.
5-{[(4-Iodophenyl)amino]methylene}-2,2-dimethyl-1,3-di-
oxane-4,6-dione (3j)
Starting from Meldrum’s acid 2 (4.77 g, 33.10 mmol), trimethyl
orthoformate (63.3 mL, 570.00 mmol), and 4-iodoaniline (1j, 5.00
g, 22.80 mmol), 3j was isolated as a yellow solid (4.51 g, 53%); mp
208–210 °C.
IR (KBr): 3197 (br, m), 3058 (m), 2992 (m), 1724 (s), 1677 (br, s),
1623 (br, s), 1595 (s), 1463 (s), 1300 (br, s), 1200 (s), 1007 cm–1
(m).
1H NMR (250 MHz, CDCl3): d = 1.75 (s, 6 H, 2 × CH3), 2.38 (s, 3
H, CH3), 7.25 (m, 3 H, Ar), 8.58 (d, 3J = 14.0 Hz, 1 H, =CH), 11.39
(br d, 3J = 14.0 Hz, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 17.2 (CH3), 27.1 (2 × CH3), 87.8
(OCCH3), 105.3 (C), 117.6, 127.7 (CHAr), 129.9 (C), 131.4 (CHAr),
132.0, 135.2 (C), 152.5 (=CH), 163.3, 165.8 (C=O).
IR (KBr): 3213 (br, w), 3090 (w), 2993 (w), 1716 (m), 1671 (br, s),
1611 (br, s), 1573 (br, s), 1448 (br, s), 1262 (br, s), 1200 (br, s),
1661 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 6 H, 2 × CH3), 7.02 (d,
3
3J = 6.9 Hz, 2 H, Ar), 7.75 (d, J = 6.9 Hz, 2 H, Ar), 8.60 (d,
3J = 14.2 Hz, 1 H, =CH), 11.21 (br d, 3J = 14.2 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.1 (2 × CH3), 87.2 (OCCH3),
90.7, 105.4 (C), 119.7 (2 CHAr), 137.6 (C), 139.1 (2 CHAr), 152.2
(=CH), 163.4, 165.6 (C=O).
MS (EI, 70 eV): m/z (%) = 295 ([M]+, 29), 237 (100), 193 (68), 178
(59), 165 (46), 158 (29), 130 (38).
MS (EI, 70 eV): m/z (%) = 373 ([M]+, 38), 315 (100), 271 (76), 245
(17), 203 (14), 144 (44), 116 (62).
Anal. Calcd for C14H14ClNO4 (295.72): C, 56.86; H, 4.77; N, 4.74:
Found: C, 56.85; H, 4.70; N, 4.58.
Anal. Calcd for C13H12INO4 (373.14): C, 41.84; H, 3.24; N, 3.75.
Found: C, 41.82; H, 3.16; N, 3.71.
5-{[(2-Chloro-4-methylphenyl)amino]methylene}-2,2-dimeth-
yl-1,3-dioxane-4,6-dione (3h)
Starting from Meldrum’s acid 2 (7.37 g, 51.20 mmol), trimethyl
orthoformate (96.4 mL, 882.50 mmol), and 2-chloro-4-methyl-
aniline (1h; 5.00 g, 35.30 mmol), 3h was isolated as a yellow solid
(7.92 g, 76%); mp 139 °C.
5-{[(2-Bromophenyl)amino]methylene}-2,2-dimethyl-1,3-di-
oxane-4,6-dione (3k)
Starting from Meldrum’s acid 2 (6.08 g, 42.20 mmol), trimethyl
orthoformate (79.4 mL, 726.80 mmol), and 2-bromoaniline (1k;
5.00 g, 29.10 mmol), 3k was isolated as a yellow solid (6.84 g,
72%); mp 160 °C.
IR (KBr): 3187 (br, w), 3060 (w), 2986 (m), 2937 (w), 1728 (s),
1680 (br, s), 1615 (br, s), 1441 (br, s), 1270 (br, s), 1051 (m), 993
(m), 930 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 6 H, 2 × CH3), 2.36 (s, 3
H, CH3), 7.16 (d, 3J = 8.3 Hz, 1 H, Ar), 7.28 (s, 1 H, Ar), 7.29 (d,
3J = 8.3 Hz, 1 H, Ar), 8.62 (d, 3J = 14.0 Hz, 1 H, =CH), 11.62 (br d,
3J = 14.0 Hz, 1 H, NH).
IR (KBr): 3191 (br, w), 3069 (w), 2997 (m), 2942 (w), 1729 (s),
1690 (br, s), 1611 (br, s), 1438 (s), 1277 (br, s), 1020 (m), 751
cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.12–7.18
(m, 1 H, Ar), 7.41–7.43 (m, 2 H, Ar), 7.64–7.67 (m, 1 H, Ar), 8.64
(d, 3J = 14.0 Hz, 1 H, =CH), 11.64 (br d, 3J = 14.0 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3), 27.2 (2 × CH3), 88.2
(OCCH3), 105.3 (C), 116.7 (CHAr), 124.4 (C), 129.1, 130.8 (CHAr),
132.6, 137.8 (C), 151.7 (=CH), 163.6, 165.3 (C=O).
13C NMR (75 MHz, CDCl3): d = 27.2 (2 × CH3), 88.7 (OCCH3),
105.4, 114.6 (C), 117.1, 127.5, 129.1, 133.8 (CHAr), 136.4 (C),
151.9 (=CH), 163.4, 165.2 (C=O).
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

PAPER
Synthesis of Halogenated 4(1H)-Quinolones
73
MS (EI, 70 eV): m/z (%) = 325 ([M]+, 79Br, 19), 269 (100), 239 (15),
224 (59), 195 (58), 171 (16), 155 (15), 116 (71), 76 (11).
Anal. Calcd for C13H11Cl2NO4 (316.14): C, 49.39; H, 3.51; N, 4.43.
Found: C, 49.16; H, 3.46; N, 4.32.
Anal. Calcd for C13H12BrNO4 (326.14): C, 47.87; H, 3.71; N, 4.29.
Found: C, 47.78; H, 3.26; N, 4.16.
5-{[(2,3-Dichlorophenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3o)
Starting from Meldrum’s acid 2 (6.45 g, 44.80 mmol), trimethyl
orthoformate (85.0 mL, 772.50 mmol), and 2,3-dichloroaniline (1o;
5.00 g, 30.90 mmol), 3o was isolated as a colorless solid (4.44 g,
45%); mp 159 °C.
5-{[(3-Bromophenyl)amino]methylene}-1,3-dioxane-4,6-dione
(3l)
Starting from Meldrum’s acid 2 (4.20 g, 30.53 mmol), trimethyl
orthoformate (55.0 mL, 499.90 mmol), and 3-bromoaniline (1l;
2.20 mL, 20.35 mmol), 3l was isolated as a yellow solid (3.79 g,
58%); mp 164–165 °C.
IR (KBr): 3157 (br, w), 3087 (m), 2997 (w), 1724 (s), 1686 (br, s),
1618 (br, s), 1417 (s), 1291 (br, s), 1010 cm–1 (br, m).
IR (ATR): 3211 (br, w), 2988 (w), 1724 (m), 1673 (br, s), 1617 (s),
1574 (s), 1459 (s), 1196 (br, s), 1070 (m), 1010 cm–1 (br, m).
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 6 H, 2 CH3), 7.17–7.21
(m, 1 H, Ar), 7.28–7.34 (m, 1 H, Ar), 7.39–7.45 (m, 2 H, Ar), 8.60
(d, 3J = 14.1 Hz, 1 H, =CH), 11.20 (br d, 3J = 14.1 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.1 (2 × CH3), 81.1 (OCCH3),
105.4 (C), 116.7, 121.1 (CHAr), 123.8 (C), 129.7, 131.4 (CHAr),
139.1 (C), 152.4 (=CH), 163.3, 165.4 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.29–7.39
3
(m, 3 H, Ar), 8.64 (d, J = 13.8 Hz, 1 H, =CH), 11.72 (br d,
3J = 13.8 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.2 (2 × CH3), 89.4 (OCCH3),
105.5 (C), 114.7 (CHAr), 123.5 (C), 127.6, 128.3 (CHAr), 134.7,
136.8 (C), 151.7 (=CH), 163.2, 165.2 (C=O).
MS (EI, 70 eV): m/z (%) = 315 ([M]+, 12), 257 (61), 213 (100), 185
(93), 145 (25), 123 (17).
MS (EI, 70 eV): m/z (%) = 327 (M+, 81Br, 18), 325 (M+, 79Br, 18),
269 (95), 267 (95), 224 (100), 222 (98), 197 (44), 171 (12), 155
(18), 116 (54), 89 (21).
Anal. Calcd for C13H11Cl2NO4 (316.14): C, 49.39; H, 3.51; N, 4.43.
Found: C, 49.24; H, 3.37; N, 4.33.
5-{[(2,5-Dichlorophenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3p)
Starting from Meldrum’s acid 2 (6.45 g, 44.80 mmol), trimethyl
orthoformate (85.0 mL, 772.50 mmol), and 2,5-dichloroaniline (1p;
5.00 g, 30.90 mmol), 3p was isolated as a colorless solid (8.15 g,
84%); mp 186 °C.
HRMS (EI): m/z calcd for C13H12BrNO4 ([M]+, 79Br) 324.99442;
found: 324.99343.
5-{[(2,4-Dibromophenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3m)
Starting from Meldrum’s acid 2 (4.15 g, 28.90 mmol), trimethyl
orthoformate (54.0 mL, 498.20 mmol), and 2,4-dibromoaniline
(1m; 5.00 g, 19.90 mmol), 3m was isolated as a colorless solid (5.48
g, 68%); mp 184 °C.
IR (KBr): 3135 (br, w), 3091 (w), 3063 (m), 3000 (w), 1727 (s),
1690 (br, s), 1625 (br, s), 1442 (s), 1202 (br, s), 1101 (s), 826 cm–1
(s).
IR (KBr): 3096 (m), 3067 (m), 2987 (m), 1725 (s), 1677 (br, s),
1601 (br, s), 1435 (br, s), 1389 (m), 1279 (br, s), 1199 (br, s), 999
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.18 (d,
3
3J = 8.6 Hz, 1 H, Ar), 7.42 (d, J = 8.6 Hz, 1 H, Ar), 7.44 (s, 1 H,
Ar), 8.61 (d, 3J = 13.8 Hz, 1 H, =CH), 11.62 (br d, 3J = 13.8 Hz, 1
H, NH).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.29 (d,
3J = 8.5 Hz, 1 H, Ar), 7.54 (dd, J = 8.5 Hz, 4J = 2.1 Hz, 1 H, Ar),
13C NMR (75 MHz, CDCl3): d = 27.2 (2 × CH3), 89.6 (OCCH3),
105.6 (C), 116.9 (CHAr), 122.7 (C), 126.9, 131.4 (CHAr), 134.4,
136.0 (C), 151.3 (=CH), 163.1, 165.1 (C=O).
3
4
3
7.79 (d, J = 2.1 Hz, 1 H, Ar), 8.59 (d, J = 13.8 Hz, 1 H, =CH),
11.60 (br d, 3J = 13.8 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 27.2 (2 × CH3), 89.2 (OCCH3),
105.5, 115.1 (C), 118.0 (CHAr), 119.6 (C), 132.1 (CHAr), 135.7 (C),
136.0 (CHAr), 151.5 (=CH), 163.2, 165.2 (C=O).
MS (EI, 70 eV): m/z (%) = 315 ([M]+, 12), 257 (50), 212 (80), 178
(100), 150 (27), 123 (17).
Anal. Calcd for C13H11Cl2NO4 (316.14): C, 49.39; H, 3.51; N, 4.43.
Found: C, 49.39; H, 2.96; N, 4.34.
MS (EI, 70 eV): m/z (%) = 403 ([M]+, 10), 347 (96), 303 (98), 275
(63), 251 (33), 222 (100), 194 (54), 169 (14), 115 (43).
2,2-Dimethyl-5-{[(2,4,5-trichlorophenyl)amino]methylene}-1,3-
dioxane-4,6-dione (3q)
Starting from Meldrum’s acid 2 (4.41 g, 30.60 mmol), trimethyl
orthoformate (60.4 mL, 552.50 mmol), and 2,4,5-trichloroaniline
(1q; 4.34 g, 22.10 mmol), 3q was isolated as a colorless solid (5.80
g, 75%); mp 225 °C.
Anal. Calcd for C13H11Br2NO4 (405.04): C, 38.55; H, 2.74; N, 3.46:
Found: C, 38.44; H, 2.59; N, 3.38.
5-{[(2,4-Dichlorophenyl)amino]methylene}-2,2-dimethyl-1,3-
dioxane-4,6-dione (3n)
Starting from Meldrum’s acid 2 (6.45 g, 44.80 mmol), trimethyl
orthoformate (85.0 mL, 772.50 mmol), and 2,4-dichloroaniline (1n;
5.00 g, 30.90 mmol), 3n was isolated as a colorless solid (7.81 g,
80%); mp 193 °C.
IR (KBr): 3125 (w), 3081 (w), 3053 (m), 3003 (m), 1724 (s), 1675
(br, s), 1625 (br, s), 1434 (s), 1287 (br, s), 917 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.56 (s, 1
H, Ar), 7.60 (s, 1 H, Ar), 8.58 (d, 3J = 13.4 Hz, 1 H, =CH), 11.59 (br
d, 3J = 13.4 Hz, 1 H, NH).
IR (KBr): 3148 (br, m), 3075 (m), 2999 (br, w), 1724 (s), 1685 (br,
s), 1618 (br, s), 1443 (br, s), 1289 (br, s), 1206 (s), 1103 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 6 H, 2 × CH3), 7.37 (m, 2
H, Ar), 7.51 (s, 1 H, Ar), 8.62 (d, 3J = 13.8 Hz, 1 H, =CH), 11.64 (br
d, 3J = 13.8 Hz, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 27.2 (2 × CH3), 90.0 (OCCH3),
105.7 (C), 118.0 (CHAr), 123.1, 130.2 (C), 131.5 (CHAr), 132.9,
134.6 (C), 151.1 (=CH), 163.0, 165.1 (C=O).
13C NMR (75 MHz, CDCl3): d = 27.2 (2 × CH3), 89.4 (OCCH3),
105.5 (C), 117.5 (CHAr), 125.3 (C), 128.7, 130.3 (CHAr), 132.0,
133.9 (C), 151.5 (=CH), 163.2, 165.2 (C=O).
MS (EI, 70 eV): m/z (%) = 351 ([M]+, 11), 293 (51), 248 (80), 212
(100), 184 (20), 157 (11).
Anal. Calcd for C13H10Cl3NO4 (350.58): C, 44.54; H, 2.88, N, 4.00.
Found: C, 44.62; H, 2.83; N, 3.83.
MS (CI, pos.): m/z (%) = 316 ([M + H]+, 100).
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

74
S. Rotzoll et al.
PAPER
4(1H)-Quinolones 4a–q; General Procedure
IR (KBr): 3173 (br, w), 3104 (br, m), 2972 (br, m), 1608 (m), 1560
(br, s), 1519 (br, s), 1450 (m), 1209 (s), 1021 (m), 805 cm–1 (s).
1H NMR (400 MHz, CD3OD): d = 2.42 (s, 3 H, CH3), 2.83 (s, 3 H,
CH3), 6.22 (d, 3J = 7.3 Hz, 1 H, CH), 6.92 (d, 3J = 7.4 Hz, 1 H, Ar),
7.26 (d, 3J = 7.4 Hz, 1 H, Ar), 7.75 (d, 3J = 7.3 Hz, 1 H, CH).
13C NMR (100 MHz, CD3OD): d = 17.5, 24.1 (CH3), 111.7 (CH),
125.0, 125.5 (C), 127.2, 133.4 (CH), 139.1 (C), 139.5 (CH), 141.6,
183.7 (C).
A mixture of the respective starting material 3a–q (1.0 equiv) and
diphenyl ether (2 mL per 1 mmol of 3) was heated under reflux for
1 h. The solution was allowed to cool to r.t. and hexane (1 mL per 1
mmol of 3) was added. The precipitate formed was collected by fil-
tration, washed with hexane (50 mL), and dried in vacuo.
Benzo[h]quinolin-4(1H)-one (4a)
Starting from 3a (5.00 g, 16.82 mmol) and diphenyl ether (34 mL),
4a was isolated as a brownish solid (2.02 g, 61%); mp 246–249 °C.
MS (EI, 70 eV): m/z (%) = 173 ([M]+, 100), 158 (14), 144 (19), 130
(39), 115 (7), 103 (6), 87 (57).
IR (KBr): 3225 (br, m), 3175 (br, m), 3051 (br, m), 1629 (br, s),
1560 (br, s), 1528 (br, s), 1426 (s), 1255 (m), 1185 (m), 807 cm–1
(br, m).
Anal. Calcd for C11H11NO (173.21): C, 76.28; H, 6.40; N, 8.08.
Found: C, 75.38; H, 6.38; N, 7.73.
1H NMR (400 MHz, DMSO-d6): d = 6.30 (br s, 1 H, CH), 7.71–7.76
(m, 3 H, Ar), 8.01–8.15 (m, 3 H, Ar), 8.69 (br s, 1 H, CH), 12.20 (br
s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 118.6, 121.6, 122.0 (CH),
122.5, 123.4 (C), 123.5, 126.8 (CH), 128.4 (C), 128.6, 130.0 (CH),
134.2 (C), 138.4 (CH), 176.6 (C).
5,7-Dimethylquinolin-4(1H)-one (4e)
Starting from 3d (5.00 g, 16.16 mmol) and diphenyl ether (36 mL),
4e was isolated as a brownish solid (2.39 g, 76%); mp 183–189 °C.
IR (KBr): 3066 (br, w), 2915 (br, m), 2810 (br, m), 1614 (s), 1556
(s), 1511 (s), 1423 (m), 1240 (m), 1116 (m), 829 cm–1 (s).
1H NMR (300 MHz, CD3OD): d = 2.39 (s, 3 H, CH3), 2.84 (s, 3 H,
CH3), 6.17 (d, 3J = 7.3 Hz, 1 H, CH), 6.91 (s, 1 H, Ar), 7.10 (s, 1 H,
Ar), 7.72 (d, 3J = 7.3 Hz, 1 H, CH).
13C NMR (75 MHz, CD3OD): d = 21.5, 23.9 (CH3), 111.4, 116.7
(CH), 123.5 (C), 129.4, 139.5 (CH), 141.1, 143.5, 183.2 (C).
MS (EI, 70 eV): m/z (%) = 195 ([M]+, 100), 167 (30), 149 (6), 139
(16), 127 (7), 97 (14), 84 (26).
HRMS (EI): m/z calcd for C13H9NO ([M]+): 195.06787; found:
195.06752.
MS (EI, 70 eV): m/z (%) = 173 ([M]+, 100), 158 (9), 143 (20), 130
(13), 115 (19), 102 (7), 86 (63).
HRMS (EI): m/z calcd for C11H11NO ([M]+): 173.08352; found:
173.08385.
8-Phenylquinolin-4(1H)-one (4b)
Starting from 3b (1.50 g, 4.64 mmol) and diphenyl ether (10 mL),
4b was isolated as a brownish solid (0.77 g, 75%); mp 201–203 °C.
IR (KBr): 3173 (br, m), 3060 (m), 3029 (m), 1619 (m), 1560 (br, m),
1441 (br, m), 1337 (br, m), 1179 (m), 751 (s), 695 cm–1 (s).
1H NMR (300 MHz, acetone-d6): d = 6.07 (d, 3J = 7.5 Hz, 1 H, CH),
7.39 (dd, 3J = 7.5 Hz, 3J = 7.5 Hz, 1 H, Ar), 7.46–7.54 (m, 6 H, Ar),
7.79 (d, 3J = 7.5 Hz, 1 H, CH), 8.25 (dd, 3J = 7.5 Hz, 4J = 1.6 Hz, 1
H, Ar), 9.97 (br s, 1 H, NH).
13C NMR (75 MHz, acetone-d6): d = 110.0, 123.6, 126.0 (CH),
127.7 (C), 129.2, 130.1, 130.4 (CH), 132.4 (C), 133.3 (CH), 137.9
(C), 139.9 (CH), 178.3 (C).
5,6,8-Trimethylquinolin-4(1H)-one (4f)
Starting with 3f (11.80 g, 40.79 mmol) and diphenyl ether (72 mL),
4f was isolated as a brownish solid (6.10 g, 90%); mp 153 °C.
IR (ATR): 3067 (br, m), 2966 (m), 2917 (br, m), 1556 (br, m), 1485
(m), 1231 (br, m), 746 (br, m), 688 cm–1 (br, m).
1H NMR (300 MHz, DMSO-d6): d = 2.24 (s, 3 H, CH3), 2.37 (s, 3
H, CH3), 2.74 (s, 3 H, CH3), 5.95 (d, 3J = 7.5 Hz, 1 H, CH), 7.26 (s,
1 H, Ar), 7.64 (d, 3J = 7.5 Hz, 1 H, CH), 10.65 (br s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 221 ([M]+, 100), 193 (35), 165 (13), 139
13C NMR (75 MHz, DMSO-d6): d = 17.1, 17.2, 19.8 (CH3), 110.6
(CH), 122.5, 124.2, 130.5 (C), 134.2 (CH), 134.4 (C), 137.3 (CH),
138.5 (C), 180.2 (C).
MS (EI, 70 eV): m/z (%) = 187 ([M]+, 100), 172 (34), 158 (8), 144
(12), 115 (6), 91 (5).
(6), 95 (9), 83 (7).
Anal. Calcd for C15H11NO (221.25): C, 81.43; H, 5.01; N, 6.33.
Found: C, 81.52; H, 5.08; N, 6.05.
6-tert-Butylquinolin-4(1H)-one (4c)
Starting from 3c (3.50 g, 11.54 mmol) and diphenyl ether (24 mL),
4b was isolated as a brownish solid (1.28 g, 55%); mp 290–297 °C.
Anal. Calcd for C12H13NO (187.24): C, 76.98; H, 7.00; N, 7.48.
Found: C, 76.69; H, 7.11; N, 7.23.
IR (KBr): 3054 (br, w), 2960 (m), 2867 (m), 1637 (m), 1595 (br, m),
1542 (br, m), 1486 (br, s), 1362 (br, m), 1203 (br, m), 1157 (m), 824
cm–1 (br, s).
6-Chloro-8-methylquinolin-4(1H)-one (4g)
Starting from 3g (3.50 g, 11.86 mmol) and diphenyl ether (24 mL),
4g was isolated as a brownish solid (1.58 g, 69%); mp 285–295 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.33 (s, 9 H, 3CH3), 6.02 (d,
3
3J = 7.4 Hz, 1 H, CH), 7.50 (d, J = 8.8 Hz, 1 H, Ar), 7.75 (dd,
IR (KBr): 3079 (br, m), 2969 (br, m), 2909 (br, m), 1549 (br, s),
1511 (br, s), 1455 (s), 1429 (s), 1256 (m), 1192 (s), 791 cm–1 (br, s).
4
3
3J = 8.8 Hz, J = 2.2 Hz, 1 H, Ar), 7.87 (d, J = 7.4 Hz, 1 H, CH),
8.06 (d, 4J = 2.2 Hz, 1 H, Ar), 11.73 (br s, 1 H, NH).
1H NMR (300 MHz, DMSO-d6): d = 2.52 (s, 3 H, CH3), 6.12 (d,
13C NMR (75 MHz, DMSO-d6): d = 31.0 (3 CH3), 34.4 (CCH3),
108.4, 118.1, 119.9 (CH), 125.3 (C), 129.7 (CH), 138.0 (C), 139.0
(CH), 145.5, 176.9 (C).
MS (EI, 70 eV): m/z (%) = 201 ([M]+, 29), 186 (100), 170 (6), 158
(12), 146 (7), 115 (4).
4
3J = 7.4 Hz, 1 H, CH), 7.57 (d, J = 2.5 Hz, 1 H, Ar), 7.86 (d,
3J = 7.4 Hz, 1 H, CH), 7.90 (d, 4J = 2.5 Hz, 1 H, Ar), 11.29 (br s, 1
H, NH).
13C NMR (75 MHz, DMSO-d6): d = 16.9 (CH3), 109.0, 121.6 (CH),
126.7, 127.3, 129.7 (C), 131.9 (CH), 137.4 (C), 139.8 (CH), 175.9
(C).
Anal. Calcd for C13H15NO (201.26): C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.55; H, 7.60; N, 6.74.
MS (EI, 70 eV): m/z (%) = 193 ([M]+, 100), 165 (15), 158 (26), 130
(30), 102 (10), 77 (8).
5,8-Dimethylquinolin-4(1H)-one (4d)
Starting from 3d (5.00 g, 16.16 mmol) and diphenyl ether (36 mL),
4d was isolated as a brownish solid (2.18 g, 67%); mp 208–210 °C.
Anal. Calcd for C10H8ClNO (193.63): C, 62.03; H, 4.16; N, 7.23.
Found: C, 62.22; H, 4.11; N, 6.97.
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

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Synthesis of Halogenated 4(1H)-Quinolones
75
8-Chloro-6-methylquinolin-4(1H)-one (4h)
Starting from 3h (3.50 g, 11.86 mmol) and diphenyl ether (24 mL),
4h was isolated as a brownish solid (1.66 g, 72%); mp 240–243 °C.
13C NMR (75 MHz, CD3OD): d = 110.5 (CH), 112.9 (C), 125.7,
126.2 (CH), 128.1 (C), 137.0 (CH), 139.1 (C), 141.9 (CH), 180.3
(C).
IR (KBr): 3105 (br, m), 3044 (m), 2941 (br, m), 2839 (br, m), 1602
(s), 1562 (br, s), 1510 (br, s), 1402 (m), 1349 (m), 1310 (s), 1222 (s),
800 (br, m), 534 cm–1 (m).
MS (EI, 70 eV): m/z (%) = 223 ([M]+, 100), 195 (51), 169 (2), 116
(48), 89 (27), 63 (16).
Anal. Calcd for C9H6BrNO (224.05): C, 48.25; H, 2.70; N, 6.25.
Found: C, 48.55; H, 2.57; N, 6.15.
1H NMR (300 MHz, CD3OD): d = 2.45 (s, 3 H, CH3), 6.33 (d,
4
3J = 7.4 Hz, 1 H, CH), 7.64 (d, J = 1.5 Hz, 1 H, Ar), 7.93 (d,
3J = 7.4 Hz, 1 H, CH), 7.96 (d, 4J = 1.5 Hz, 1 H, Ar).
7-Bromoquinolin-4(1H)-one (4l-A) and 5-Bromoquinolin-
4(1H)-one (4l-B)
Starting from 3l (4.00 g, 12.31 mmol) and diphenyl ether (25 mL),
a mixture of 4l-A und 4l-B (1.6:1) was isolated as a brownish solid
(2.00 g, 73%).
13C NMR (75 MHz, CD3OD): d = 21.0 (CH3), 110.2 (CH), 123.0
(C), 124.7 (CH), 127.9 (C), 134.6 (CH), 135.9, 136.2 (C), 141.4
(CH), 180.1 (C).
MS (EI, 70 eV): m/z (%) = 193 ([M]+, 100), 164 (20), 130 (36), 102
(10), 77 (9), 64 (10).
4l-A
1H NMR (300 MHz, DMSO-d6): d = 6.07 (d, 3J = 7.4 Hz, 1 H, CH),
7.44 (dd, 3J = 8.6 Hz, 4J = 1.8 Hz, 1 H, Ar), 7.75 (d, 4J = 1.8 Hz, 1
H, Ar), 7.93 (d, 3J = 7.4 Hz, 1 H, CH), 8.00 (d, 3J = 8.6 Hz, 1 H, Ar),
11.80 (br s, 1 H, NH).
Anal. Calcd for C10H8ClNO (193.63): C, 62.03; H, 4.16; N, 7.23.
Found: C, 61.85; H, 4.10; N, 7.01.
8-(Trifluoromethyl)quinolin-4(1H)-one (4i)
Starting from 3i (3.00 g, 9.28 mmol) and diphenyl ether (20 mL), 4i
was isolated as a brownish solid (1.72 g, 84%); mp 170–172 °C.
4l-B
1H NMR (300 MHz, DMSO-d6): d = 6.03 (d, 3J = 7.4 Hz, 1 H, CH),
7.42–7.55 (m, 3 H, Ar), 7.84 (d, 3J = 7.4 Hz, 1 H, CH), 11.80 (br s,
1 H, NH).
IR (KBr): 3187 (br, m), 3077 (br, m), 3036 (br, m), 1631 (m), 1579
(br, m), 1520 (m), 1448 (br, m), 1304 (br, m), 1104 (s), 1084 (s), 748
(s), 716 cm–1 (s).
1H NMR (300 MHz, acetone-d6): d = 6.29 (d, 3J = 7.6 Hz, 1 H, CH),
7.49–7.54 (m, 1 H, Ar), 8.02 (d, 3J = 7.6 Hz, 1 H, CH), 8.06–8.09
(m, 1 H, Ar), 8.54–8.58 (m, 1 H, Ar), 10.65 (br s, 1 H, NH).
6,8-Dibromoquinolin-4(1H)-one (4m)
Starting from 3m (5.00 g, 12.35 mmol) and diphenyl ether (26 mL),
4m was isolated as a brownish solid (2.02 g, 52%); mp 291 °C.
13C NMR (75 MHz, acetone-d6): d = 111.0 (CH), 119.7 (q,
1JF,C = 245 Hz, CF3), 123.2 (CH), 126.9, 128.1 (C), 130.6, 131.6
(CH), 137.8 (C), 141.2 (CH), 178.3 (C).
MS (EI, 70 eV): m/z (%) = 213 ([M]+, 100), 193 (65), 184 (5), 165
(87), 138 (13), 114 (4), 83 (10).
IR (KBr): 3066 (br, m), 2920 (br, m), 1586 (br, s), 1547 (br, s), 1507
(br, s), 1427 (s), 1299 (m), 1188 (s), 1116 (m), 802 cm–1 (br, s).
1H NMR (300 MHz, DMSO-d6): d = 6.28 (d, 3J = 7.5 Hz, 1 H, CH),
8.00 (d, 3J = 7.5 Hz, 1 H, CH), 8.28 (d, 4J = 2.3 Hz, 1 H, Ar), 8.33
(d, 4J = 2.3 Hz, 1 H, Ar), 11.43 (br s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 109.6 (CH), 112.9, 115.4 (C),
Anal. Calcd for C10H6F3NO (213.16): C, 56.35; H, 2.84; N, 6.57.
Found: C, 56.51; H, 2.79; N, 6.33.
127.2 (CH), 127.8, 136.8 (C), 136.9, 140.7 (CH), 175.2 (C).
MS (EI, 70 eV): m/z (%) = 303 ([M]+, 100), 275 (40), 222 (19), 194
(27), 131 (25), 115 (57).
6-Iodoquinolin-4(1H)-one (4j)
Starting from 3j (4.50 g, 12.05 mmol) and diphenyl ether (25 mL),
4j was isolated as a brownish solid (2.71 g, 83%); mp 275–281 °C.
Anal. Calcd for C9H5Br2NO (302.95): C, 35.68; H, 1.66; N, 4.62.
Found: C, 35.75; H, 1.49; N, 4.60.
IR (KBr): 3055 (br, m), 2955 (br, m), 2805 (br, m), 1600 (br, m),
1544 (br, s), 1501 (br, s), 1460 (br, s), 1392 (m), 1199 (br, s), 1142
(m), 807 cm–1 (s).
1H NMR (300 MHz, DMSO-d6): d = 6.08 (d, 3J = 7.4 Hz, 1 H, CH),
7.37 (d, 3J = 8.7 Hz, 1 H, Ar), 7.91 (dd, 3J = 8.7 Hz, 4J = 2.0 Hz, 1
H, Ar), 7.94 (d, 3J = 7.4 Hz, 1 H, CH), 8.37 (d, 4J = 2.0 Hz, 1 H, Ar),
11.91 (br s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 109.1 (CH), 118.6 (C), 120.8
(CH), 127.5, 130.0 (C), 133.4 139.6, 139.8 (CH), 175.4 (C).
MS (EI, 70 eV): m/z (%) = 271 ([M]+, 100), 144 (32), 116 (20), 105
(16), 97 (11), 77 (14).
6,8-Dichloroquinolin-4(1H)-one (4n)
Starting from 3n (5.40 g, 15.41 mmol) and diphenyl ether (32 mL),
4n was isolated as a brownish solid (2.56 g, 78%); mp 290 °C.
IR (KBr): 3140 (w), 3083 (m), 2928 (w), 1620 (br, m), 1560 (br, s),
1511 (s), 1337 (s), 1213 (s), 1080 cm–1 (m).
1H NMR (400 MHz, DMSO-d6): d = 6.18 (d, 3J = 7.5 Hz, 1 H, CH),
7.90 (d, 3J = 7.5 Hz, 1 H, CH), 8.00 (d, 4J = 2.4 Hz, 1 H, Ar), 7.01
(d, 4J = 2.4 Hz, 1 H, Ar), 11.55 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6/CD3OD): d = 108.7, 122.6 (CH),
126.4, 127.1 (C), 130.6 (CH), 134.7 (C), 139.7 (CH), 177.5 (C).
MS (EI, 70 eV): m/z (%) = 213 ([M]+, 100), 185 (55), 150 (21), 123
(14), 93 (9).
Anal. Calcd for C9H6INO (271.05): C, 39.88; H, 2.23; N, 5.17.
Found: C, 39.88; H, 2.20; N, 4.94.
Anal. Calcd for C9H5Cl2NO (214.05): C, 50.50; H, 2.35; N, 6.54.
Found: C, 50.45; H, 2.30; N, 6.48.
8-Bromoquinolin-4(1H)-one (4k)
Starting from 3k (6.00 g, 18.40 mmol) and diphenyl ether (38 mL),
4k was isolated as a brownish solid (2.89 g, 70%); mp 174 °C.
7,8-Dichloroquinolin-4(1H)-one (4o)
Starting from 3o (3.77 g, 10.77 mmol) and diphenyl ether (22 mL),
4o was isolated as a brownish solid (1.43 g, 62%); mp 303 °C.
IR (KBr): 3150 (m), 3080 (m), 2934 (m), 1626 (m), 1605 (s), 1556
(br, s), 1516 (s), 1433 (m), 1335 (m), 798 cm–1 (br, m).
1H NMR (300 MHz, DMSO-d6): d = 6.13 (d, 3J = 7.4 Hz, 1 H, CH),
IR (KBr): 3126 (w), 3071 (m), 2934 (w), 1623 (br, m), 1600 (s),
1588 (s), 1552 (br, s), 1335 (m), 1189 cm–1 (s).
7.26 (dd, 3J = 7.8 Hz, 3J = 7.9 Hz, 1 H, Ar), 7.86 (d, 3J = 7.4 Hz, 1
3
4
H, CH), 7.98 (dd, J = 7.9 Hz, J = 1.4 Hz, 1 H, Ar), 8.11 (d,
3J = 7.8 Hz, 4J = 1.4 Hz, 1 H, Ar), 11.15 (br s, 1 H, NH).
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S. Rotzoll et al.
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1H NMR (400 MHz, DMSO-d6): d = 6.17 (d, 3J = 7.5 Hz, 1 H, CH),
7.54 (d, 3J = 8.7 Hz, 1 H, Ar), 7.89 (d, 3J = 7.5 Hz, 1 H, CH), 8.06
(d, 3J = 8.7 Hz, 1 H, Ar), 11.25 (br s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6/CD3OD): d = 110.3 (CH), 120.4
(C), 124.6, 125.6 (CH), 130.3, 135.8, 138.2 (C), 140.9 (CH), 177.1
(C).
1H NMR (300 MHz, CDCl3): d = 4.09 (s, 3 H, OCH3), 6.28 (d,
3J = 8.5 Hz, 1 H, CH), 7.61 (dd, 4J = 2.5 Hz, 3J = 9.4 Hz, 1 H, Ar),
8.33 (d, 4J = 2.5 Hz, 1 H, Ar), 8.36 (d, 3J = 8.5 Hz, 1 H, CH), 8.65
(d, 3J = 9.4 Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 55.4 (OCH3), 112.6, 121.9, 126.0
(CH), 127.8, 131.8 (C), 133.0 (CH), 136.8 (C), 138.4 (CH), 151.7
(NCO), 177.7 (C=O).
MS (EI, 70 eV): m/z (%) = 213 ([M]+, 100), 185 (83), 150 (23), 123
(17), 93 (14).
MS (EI, 70 eV): m/z (%) = 239 (M+, 37Cl, 16), 237 (M+, 35Cl, 53),
193 (59), 178 (17), 150 (100), 123 (52).
Anal. Calcd for C9H5Cl2NO (214.05): C, 50.50; H, 2.35; N, 6.54.
Found: C, 50.34; H, 2.29; N, 6.42.
Anal. Calcd for C11H8ClNO3 (237.02): C, 55.60; H, 3.39; N, 5.89.
Found: C, 55.70; H, 3.38; N, 5.74.
5,8-Dichloroquinolin-4(1H)-one (4p)
Starting from 3p (6.00 g, 18.98 mmol) and diphenyl ether (38 mL),
6-Bromo-1-methoxycarbonyl-4-quinolone (6b)
4p was isolated as a brownish solid (2.52 g, 61%); mp 268 °C.
Starting from 6-bromoquinolin-4(1H)-one (0.835 g, 3.73 mmol),
NaH (0.233 g, 9.70 mmol), THF (17.0 mL), and methyl chlorofor-
mate (0.900 g, 9.50 mmol), 6b was isolated as a colorless solid (882
mg, 84%); mp 143–144 °C.
IR (KBr): 3092 (m), 3046 (m), 2953 (m), 1625 (s), 1590 (br, s),
1559 (s), 1502 (s), 1396 (m), 1205 (s), 808 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 6.10 (d, 3J = 7.5 Hz, 1 H, CH),
7.27 (d, 3J = 8.4 Hz, 1 H, Ar), 7.74 (d, 3J = 8.4 Hz, 1 H, Ar), 7.77 (d,
3J = 7.5 Hz, 1 H, CH), 11.25 (br s, 1 H, NH).
IR (KBr): 3438 (br, w), 3100 (m), 3071 (m), 2952 (m), 1750 (s),
1662 (s), 1640 (s), 1593 (s), 1554 (w), 1267 (s), 1432 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 4.08 (s, 3 H, OCH3), 6.26 (d,
3J = 8.5 Hz, 1 H, CH), 7.73 (dd, 3J = 9.5 Hz, 4J = 2.4 Hz, 1 H, Ar),
8.35 (d, 3J = 8.5 Hz, 1 H, CH), 8.46 (d, 4J = 2.4 Hz, 1 H, Ar), 8.56
(d, 3J = 9.5 Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 55.4 (OCH3), 112.6 (CH), 119.5
(C), 122.0 (CH), 127.9 (C), 129.1 135.8 (CH), 137.2 (C), 138.4
(CH), 151.6 (NCO), 177.5 (C=O).
NMR (75 MHz, DMSO-d6): d = 111.8 (CH), 120.6, 122.6 (C),
125.6, 131.4 (CH), 138.7 (C), 138.8 (CH), 175.8 (C).
MS (EI, 70 eV): m/z (%) = 213 ([M]+, 100), 185 (51), 150 (19), 123
(13), 93 (10).
Anal. Calcd for C9H5Cl2NO (214.05): C, 50.50; H, 2.35; N, 6.54.
Found: C, 50.45; H, 2.09; N, 6.48.
MS (EI, 70 eV): m/z (%) = 283 (M+, 81Br, 97), 281 (M+, 79Br, 100),
239 (17), 237 (17), 211 (12), 209 (14), 196 (20), 194 (20), 130 (11),
128 (8).
5,6,8-Trichloroquinolin-4(1H)-one (4q)
Starting from 3q (5.80 g, 16.54 mmol) and diphenyl ether (34 mL),
4q was isolated as a brownish solid (2.88 g, 71%); mp 318 °C.
Anal. Calcd for C11H8BrNO3 (280.97): C, 46.84; H, 2.86; N, 4.97.
Found: C, 46.77; H, 2.87; N, 4.72.
IR (KBr): 3084 (m), 3015 (br, m), 2949 (m), 2887 (m), 1625 (br, m),
1601 (br, s), 1566 (br, s), 1497 (s), 1427 (s), 1210 (s), 1086 (m), 803
cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 6.16 (d, 3J = 7.5 Hz, 1 H, CH),
7.81 (d, 3J = 7.4 Hz, 1 H, CH), 8.18 (s, 1 H, Ar), 11.30 (br s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 112.2 (CH), 124.4, 127.2 129.0
(C), 131.8 (CH), 137.6 (C), 138.8 (CH), 175.1 (C).
MS (EI, 70 eV): m/z (%) = 247 ([M]+, 100), 219 (25), 184 (13), 142
(12), 111 (8), 97 (12).
6-Bromo-1-ethoxycarbonyl-4-quinolone (6c)
Starting from 6-bromoquinolin-4(1H)-one (1.000 g, 4.50 mmol),
NaH (0.280 g, 11.70 mmol), THF (20.0 mL), and ethyl chlorofor-
mate (1.250 g, 11.50 mmol), 6c was isolated as a yellow solid (920
mg, 70%); mp 104–106 °C.
IR (ATR): 3057 (br, w), 2977 (w), 1753 (s), 1629 (br, s), 1466 (s),
1402 (m), 1213 (br, s), 1190 (br, s), 1152 (br, s), 820 (s), 757 cm–1
(s).
3
1H NMR (300 MHz, CDCl3): d = 1.50 (t, J = 7.1 Hz, 3 H, CH3),
Anal. Calcd for C9H4Cl3NO (248.49): C, 43.50; H, 1.62; N, 5.64.
Found: C, 43.57; H, 1.59; N, 5.22.
4.54 (q, 3J = 7.1 Hz, 2 H, CH2), 6.28 (d, 3J = 8.6 Hz, 1 H, CH), 7.73
3
4
3
(dd, J = 9.4 Hz, J = 2.6 Hz, 1 H, Ar), 8.37 (d, J = 8.6 Hz, 1 H,
CH), 8.46 (d, 4J = 2.6 Hz, 1 H, Ar), 8.56 (d, 3J = 9.4 Hz, 1 H, Ar).
1-Alkoxycarbonyl-4-quinolones 6a–h; General Procedure
To a suspension of NaH (2.6 equiv) in THF (4.5 mL per 1 mmol of
4) was added portionwise the quinolone 4 (1.0 equiv) at 0 °C. The
mixture was stirred for 30 min at 50 °C and the chloroformate (2.6
equiv) was subsequently added dropwise. The solution was allowed
to cool to r.t. and stirred for 48 h. To the mixture was added aq 2 M
HCl (50 mL). The organic and the aqueous layer were separated and
the latter was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
(silica gel, heptanes–EtOAc, 1:1).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 65.4 (OCH2), 112.4
(CH), 119.4 (C), 122.1 (CH), 128.0 (C), 129.1 135.7 (CH), 137.3
(C), 138.5 (CH), 151.1 (NCO), 177.6 (C=O).
MS (EI, 70 eV): m/z (%) = 297 (M+, 81Br, 98), 295 (M+, 79Br, 99),
238 (46), 223 (100), 197 (19), 172 (9), 144 (24), 116 (43), 89 (13).
HRMS (EI): m/z calcd for C12H10BrNO4 ([M]+, 79Br): 294.98386;
found: 294.98376.
6-Fluoro-1-methoxycarbonyl-4-quinolone (6d)
Starting from 6-fluoroquinolin-4(1H)-one (0.735 g, 4.50 mmol),
NaH (0.280 g, 11.70 mmol), THF (25.0 mL), and methyl chlorofor-
mate (1.09 g, 11.70 mmol), 6d was isolated as a yellow solid (625
mg, 63%); mp 122–123 °C.
6-Chloro-1-methoxycarbonyl-4-quinolone (6a)
Starting from 6-chloroquinolin-4(1H)-one (0.637 g, 3.55 mmol),
NaH (0.221 g, 9.22 mmol), THF (17.0 mL), and methyl chlorofor-
mate (0.858 g, 9.10 mmol), 6a was isolated as a colorless solid (600
mg, 71%); mp 140–141 °C.
IR (KBr): 3206 (br, w), 3117 (m), 2959 (w), 1750 (s), 1664 (s), 1617
(s), 1480 (s), 1275 (br, s), 1242 (br, s), 1149 (m), 831 cm–1 (s).
IR (KBr): 3438 (br, w), 3106 (w), 3073 (w), 2955 (w), 1750 (s),
1662 (s), 1639 (s), 1599 (s), 1557 (m), 1469 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 4.10 (s, 3 H, OCH3), 6.27 (d,
3J = 8.5 Hz, 1 H, CH), 7.40 (m, 1 H, Ar), 8.01 (m, 1 H, Ar), 8.39 (d,
3J = 8.5 Hz, 1 H, CH), 8.73 (m, 1 H, Ar).
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Synthesis of Halogenated 4(1H)-Quinolones
77
13C NMR (75 MHz, CDCl3): d = 55.4 (OCH3), 115.5 (d,
121.1 (=CH2), 122.7 (d, 3JC,F = 7 Hz, CHAr), 128.5 (d, 3JC,F = 8 Hz,
2
4
2JC,F = 23 Hz, CHAr), 111.9 (CH), 120.9 (d, JC,F = 24 Hz, CHAr),
CAr), 130.3 (CH), 134.8 (d, JC,F = 2 Hz, CAr), 138.4 (CH), 151.0
3
3
122.7 (d, JC,F = 8 Hz, CHAr), 128.6 (d, JC,F = 7 Hz, CAr), 134.8
(CAr), 138.4 (CH), 151.8 (NCO), 159.9 (d, 1JC,F = 247 Hz, CAr), 178
(d, 4JC,F = 2 Hz, C=O).
(NCO), 159.8 (d, 1JC,F = 247 Hz, CAr), 178.0 (d, 4JC,F = 2 Hz, C=O).
MS (EI, 70 eV): m/z (%) = 247 ([M]+, 39), 203 (21), 163 (11), 134
(19), 107 (19), 97 (8), 41 (100).
MS (EI, 70 eV): m/z (%) = 221 ([M]+, 100), 177 (21), 162 (10), 148
(21), 134 (34), 107 (24), 97 (6).
Anal. Calcd for C13H10FNO3 (247.22): C, 63.16; H, 4.08; N, 5.67.
Found: C, 63.10; H, 4.00; N, 5.73.
Anal. Calcd for C11H8FNO3 (221.18): C, 59.73; H, 3.65; N, 6.33.
Found: C, 59.91; H, 3.53; N, 6.28.
1-Benzyloxycarbonyl-tert-butyl-4-quinolone (6h)
Starting from 6-tert-butylquinolin-4(1H)-one (4c; 1.000 g, 5.00
mmol), NaH (0.500 g, 60% suspension in mineral oil, 12.90 mmol),
THF (25.0 mL), and benzyl chloroformate (2.200 g, 12.90 mmol),
6h was isolated as a yellow oil (751 mg, 45%).
5,7-Dichloro-1-methoxycarbonyl-4-quinolone (6e)
Starting from 5,7-dichloroquinolin-4(1H)-one (1.430 g, 6.75
mmol), NaH (0.420 g, 17.25 mmol), THF (25.0 mL), and methyl
chloroformate (1.630 g, 17.25 mmol), 6e was isolated as a yellow
solid (1.200 g, 66%); mp 147–148 °C.
IR (neat): 3031 (m), 2958 (br, s), 1755 (br, s), 1646 (br, s), 1607 (s),
1486 (br, s), 1217 (br, s), 1115 (m), 1022 (s), 828 (s), 699 cm–1 (s).
IR (KBr): 3131 (w), 3090 (w), 2971 (w), 1749 (br, s), 1666 (br, s),
1584 (s), 1249 (br, s), 1262 (m), 957 cm–1 (br, m).
1H NMR (300 MHz, CDCl3): d = 4.09 (s, 3 H, CH3), 6.19 (d,
3J = 8.6 Hz, 1 H, CH), 7.42 (d, 4J = 2.0 Hz, 1 H, Ar), 8.19 (d,
3J = 8.6 Hz, 1 H, CH), 8.59 (d, 4J = 2.0 Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 55.5 (OCH3), 114.4, 119.2 (CH),
121.8 (C), 128.9 (CH), 135.2 (C), 136.5 (CH), 137.8, 140.8 (C),
151.5 (NCO), 177.0 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 9 H, 3 × CH3), 5.46 (s, 2
3
H, CH2), 6.24 (d, J = 8.5 Hz, 1 H, CH), 7.33–7.50 (m, 5 H, Ar),
7.72 (dd, 3J = 9.2 Hz, 4J = 2.6 Hz, 1 H, Ar), 8.34 (d, 3J = 8.5 Hz, 1
H, CH), 8.36 (d, 4J = 2.6 Hz, 1 H, Ar), 8.61 (d, 3J = 9.2 Hz, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 31.0 (3 × CH3), 34.7 (CCH3), 70.4
(OCH2), 112.4, 119.8, 122.4 (CH), 126.2 (C), 128.5, 128.5, 128.6,
130.1 (CH), 136.3 (C), 137.9 (CH), 141.0, 148.7 (C), 151.3 (NCO),
179.3 (C=O).
MS (EI, 70 eV): m/z (%) = 271 ([M]+, 37Cl, 100), 227 (27), 199 (29),
MS (EI, 70 eV): m/z (%) = 335 ([M]+, 23), 291 (46), 276 (60), 201
184 (27), 149 (12), 121 (15), 91 (9).
(33), 186 (78), 158 (9), 91 (100).
Anal. Calcd for C11H7Cl2NO3 (272.08): C, 48.56; H, 2.59; N, 5.15.
Found: C, 46.69; H, 2.55; N, 4.96.
HRMS (EI): m/z calcd for C21H21NO3 ([M]+): 335.15160; found:
335.15111.
Anal. Calcd for C21H21NO3 (335.40): C, 75.26; H, 6.31; N, 4.18.
Found: C, 75.60; H, 6.74; N, 4.04.
1-Allyloxycarbonyl-5,7-dimethyl-4-quinolone (6f)
Starting from 5,7-dimethylquinolin-4(1H)-one (4e; 0.571 g, 3.30
mmol), NaH (0.210 g, 8.60 mmol), THF (17.0 mL), and allyl chlo-
roformate (0.9 mL, 8.60 mmol), 6f was isolated as a yellow solid
(667 mg, 79%); mp 72–74 °C.
References
(1) Cimino, G.; de Rosa, S.; deStefano, S.; Spinelli, A.; Sodano,
G. Tetrahedron Lett. 1984, 25, 2925.
(2) Molinski, T. F.; Faulkner, D. J. Tetrahedron Lett. 1988, 29,
2137.
(3) Royt, P. W.; Honeychuk, R. V.; Ravich, V.; Ponnaluri, P.;
Pannel, L. K.; Buyer, J. S.; Chandhoke, V.; Stalick, W. M.;
de Sesso, L. C.; Donohue, S.; Ghei, R.; Releya, J. D.; Ruiz,
R. Bioorg. Chem. 2001, 29, 387.
IR (KBr): 3138 (w), 2962 (m), 2921 (m), 1745 (br, s), 1645 (br, s),
1607 (s), 1456 (s), 1241 (br, s), 1202 (br, s), 1099 (s), 961 cm–1 (br,
s).
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 2.82 (s, 3 H,
CH3), 4.89 (m, 2 H, OCH2), 5.40 (m, 1 H, CH=CH2), 5.46 (m, 1 H,
CH=CH2), 6.00 (m, 1 H, CH=CH2), 6.27 (d, 3J = 8.5 Hz, 1 H, CH),
6.99 (s, 1 H, Ar), 8.16 (d, 3J = 8.5 Hz, 1 H, CH), 8.19 (s, 1 H, Ar).
(4) Jaquemond-Collet, I.; Bessiere, J. M.; Hannedouche, S.;
Bertrand, C.; Fouraste, I.; Moulis, C. Phytochem. Anal.
2001, 12, 312.
13C NMR (75 MHz, CDCl3): d = 22.1, 23.9 (CH3), 69.0 (OCH2),
114.2, 118.2 (CH), 120.5 (=CH2), 123.2 (C), 130.2, 130.6, 136.3
(CH), 140.2, 141.0, 142.2 (C), 151.6 (NCO), 181.2 (C=O).
(5) Wentland, M. P.; Perni, R. B.; Dorff, P. H.; Brundage, R. P.;
Castaldi, M. J.; Bailey, T. R.; Carabateas, P. M.; Bacon, E.
R.; Young, D. C.; Woods, M. G.; Rosi, D.; Drozd, M. L.;
Kullnig, R. K.; Dutko, F. J. J. Med. Chem. 1993, 36, 1580.
(6) Schmidt, R. D. Taschenatlas der Biotechnologie und
Gentechnik; Wiley-VCH Verlag: Weinheim, 2002.
(7) (a) Legros, J. Y.; Primault, G.; Fiaud, J. C. Tetrahedron
2001, 57, 2507. (b) Walker, S. D.; Barder, T.; Martinelli, J.
R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871.
(c) Wolf, C.; Kovi, K. E. Eur. J. Org. Chem. 2006, 1917.
(d) Graf, G. I.; Hastreiter, D.; da Silva, L. E.; Rebelo, R. A.;
Montalban, A. G.; McKillop, A. Tetrahedron 2002, 58,
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Chem. 1969, 6, 77.
(11) Sterling Drug Inc. British Patent 1147760, 1969; Chem.
Abstr. 1969, 71, 49967a.
MS (EI, 70 eV): m/z (%) = 257 ([M]+, 44), 172 (100), 144 (15), 115
(8), 91 (4).
Anal. Calcd for C15H15NO3 (257.11): C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.59; H, 5.87; N, 5.32.
1-Allyloxycarbonyl-6-fluoro-4-quinolone (6g)
Starting from 6-fluoroquinolin-4(1H)-one (0.540 g, 3.30 mmol),
NaH (0.210 g, 8.60 mmol), THF (25.0 mL), and allyl chloroformate
(0.9 mL, 8.60 mmol), 6g was isolated as a yellow solid (681 mg,
84%); mp 74–78 °C.
IR (KBr): 3150 (m), 3076 (m), 2986 (w), 1752 (br, s), 1640 (br, s),
1617 (s), 1476 (s), 1225 (br, s), 1196 (br, s), 1138 (s), 924 (s), 525
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 4.94 (m, 2 H, OCH2), 5.42 (m, 1
H, CH=CH2), 5.49 (m, 1 H, CH=CH2), 6.04 (m, 1 H, CH=CH2),
6.27 (d, 3J = 8.6 Hz, 1 H, CH), 7.39 (m, 1 H, Ar), 8.00 (m, 1 H, Ar),
8.39 (d, 3J = 8.6 Hz, 1 H, CH), 8.73 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 69.5 (OCH2), 111.5 (d,
2
2JC,F = 23 Hz, CHAr), 111.9 (CH), 120.9 (d, JC,F = 22 Hz, CHAr),
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York

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S. Rotzoll et al.
PAPER
(12) Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun.
1985, 15, 125.
(13) CCDC-695059 (3d), CCDC-695060 (4o) and CCDC-
695061 (6c) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(14) (a) Beifuss, U.; Schniske, U.; Feder, G. Tetrahedron 2001,
57, 1005. (b) Kocienski, P. J. Protecting Groups; Thieme:
Stuttgart, 1994.
Synthesis 2009, No. 1, 69–78 © Thieme Stuttgart · New York