Synthesis of chromones and 4-hydroxyquinolines based on uncatalyzed condensations of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene with 2-alkoxy- and 2-nitrobenzoyl chlorides and related reactions

Article abstract of DOI:10.1039/b901092k

The reaction of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene with 2-methoxybenzoyl chlorides afforded 3,5-diketoesters which were transformed, by treatment with boron tribromide, into functionalized 2-hydroxychroman-4-ones or chromones. The reaction

Full text of DOI:10.1039/b901092k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of chromones and 4-hydroxyquinolines based on uncatalyzed
condensations of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene with
2-alkoxy- and 2-nitrobenzoyl chlorides and related reactions†
Thomas Rahn,a,b Bettina Appel,a Wolfgang Baumann,b Haijun Jiao,b Armin Bo¨rner,a,b Christine Fischerb and
Peter Langer*a,b
Received 19th January 2009, Accepted 20th February 2009
First published as an Advance Article on the web 20th March 2009
DOI: 10.1039/b901092k
The reaction of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene with 2-methoxybenzoyl chlorides
afforded 3,5-diketoesters which were transformed, by treatment with boron tribromide, into
functionalized 2-hydroxychroman-4-ones or chromones. The reaction of 1-methoxy-1,3-bis-
(trimethylsilyloxy)-1,3-butadiene with 2-nitrobenzoyl chlorides and subsequent reduction of the nitro
group afforded functionalized 4-hydroxyquinolines. Their tautomeric equilibrium was studied by NMR
spectroscopy and by computational methods.
prepared based on the condensation of 1,3-bis(silyloxy)-1,3-
butadienes with chloroacetyl chloride.11 Recently, we have re-
Introduction
Poly(b-oxo)esters occur in various pharmacologically relevant
natural products (polyketides) and represent useful synthetic
building blocks.1 Harris and coworkers and others studied the syn-
thesis of condensation of 1,3-dicarbonyl dianions2 with carboxylic
acid derivatives.3–5 In most cases esters have been used. Their
replacement by N-acyl-2-methylaziridines6 and Weinreb amides
proved to be advantageous in several cases.7 However, several
functionalized derivatives fail to give the desired condensation
products, especially when simple carboxylic esters are used. For
example, the reaction of 1,3-dicarbonyl dianions with nitro-
substituted benzoates results in reduction of the nitro group and
decomposition. The reaction of dianions with a,b-unsaturated
esters results in a 1,4- rather than 1,2-addition. 1,3-Dicarbonyl
dianions are not only strong nucleophiles, but also strong bases
and reducing agents. Therefore, several side-reactions, such as
proton transfer, eliminations, O-acylations, SET-processes, over-
addition, and decomposition, are possible for dianions (in contrast
to reactions of simple enolate monoanions).
1,3-Bis(silyloxy)-1,3-butadienes can be regarded as electroneu-
tral equivalents of 1,3-dicarbonyl dianions and their synthetic
application allows circumvention of the problems mentioned
above for the use of free dianions.8 Reactions of 1,3-bis(silyloxy)-
1,3-butadienes and related compounds with carboxylic acid
derivatives have been studied. Chan and coworkers reported the
synthesis of functionalized phenols by formal [5 + 1] cyclization
of 1-methoxy-1,3,5-tris(trimethylsilyloxy)-1,3,5-hexatriene with
acid chlorides.9 We have recently reported the synthesis of
resorcins by cyclization of 1,3-bis(silyloxy)-1,3-butadienes with
3,3-dimethoxypentanoyl chloride.10 3(2H)-Furanones have been
ported the synthesis of 3,5-dioxoesters by condensation of
1,3-bis(silyloxy)-1,3-butadienes with acid chlorides.12,13 This work
includes reactions of aromatic, aliphatic, and a,b-unsaturated
acid chlorides. In addition, 3,5-dioxopimelic acid diesters, stable
1,3,5,7-tetracarbonyl derivatives, have been prepared by reaction
of 1,3-bis(silyloxy)-1,3-butadienes with methyl malonyl chloride.14
Herein, we report, for the first time, the synthesis of functionalized
2-hydroxychroman-4-ones, chromones, and 4-hydroxyquinolines
by reaction of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
with 2-alkoxy- and 2-nitrobenzoyl chlorides.
Results and discussion
Reactions of 2-alkoxybenzoyl chlorides
The condensation of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
butadiene (1) with 2-alkoxybenzoyl chlorides 2a–e afforded the
5-(2-alkoxyphenyl)-3,5-dioxoesters 3a–e which mainly or exclu-
sively exist in the form of their enol tautomers (Table 1). The
dashed line indicates that there is a fast equilibrium between two
enolic forms. Similar to acetylacetone, only one set of signals is
observed by NMR. The best yields were obtained, in analogy to
our previous studies,12a,13,14 when the condensations were carried
out in the absence of any Lewis acid. The formation of 3a–e
presumably proceeds by attack of the terminal carbon atom of 1
onto the acid chloride. This step might be catalyzed by a catalytic
amount of HCl formed by hydrolysis of the acid chloride. The
reaction works equally well using commercially available (new
bottle) or freshly distilled 2a. However, the yields significantly
dropped when the acid chloride was too old.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str., 3a, 18059,
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: +49 381
49864112; Tel: +49 381 4986410
Treatment of 3a and 3c with BBr3 and subsequent addition
of water afforded the chromones 5a and 5c in good yields,
respectively. The reaction of BBr3 with 3b, containing two ethoxy
substituents, was unsuccessful (no conversion). This might be
explained by interaction of the additional ethoxy group with the
Lewis acid. The reaction of BBr3 with 3d and 3e afforded the
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059, Rostock, Germany
† Electronic supplementary information (ESI) available: NMR spectra.
See DOI: 10.1039/b901092k
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Table 1 Synthesis of 4d,e and 5a,c,f
3–5
R1
R2
R3
R4
Keto/Enol
% (3)a
% (4)a
% (5)a
a
b
c
d
e
H
H
H
H
H
OEt
Cl
H
H
H
Cl
H
Me
Et
Me
Me
Et
14 : 86
0 : 100
0 : 100
0 : 100
0 : 100
45
55
84
85
36
0
0
76
0
73
37 b
0
0
H
37b
53
–C4H4–
a Yields of isolated products; 3a: keto/enol = 14 : 86, 3b–e: keto/enol = 0 : 100. b 4d/5d = 2 : 1.
2-hydroxychroman-4-ones 4d and 4e, respectively. All attempts to
transform 4d,e into the corresponding chromones 5d,e by acid-
mediated elimination of water failed (decomposition). The reason
for the influence of the substituents on the type of product remains
unclear at present. It was shown that the surprising results are
reproducible.
Reactions of 2-nitrobenzoyl chlorides
The reaction of 1 with 2-nitrobenzoyl chlorides 6a–g afforded the
condensation products 7a–g (Table 2). The hydrogenation (H2,
Pd/C 10 mol%, MeOH) of 7a,b, and 7d–g afforded the quinolines
8a,b, and 8d–g, respectively. The formation of 8c from 7c could
be detected, however, the pure product could not be isolated,
due to problems related to the chromatographic purification. The
Scheme 1 Selected tautomeric structures of 8f.
formation of products 8 can be explained by reduction of the nitro
to an amino group and subsequent cyclization by attack of the
amino onto the carbonyl group and extrusion of water.
Several tautomeric structures are possible for products 8a–g
(Scheme 1). Tautomers A and D contain a 4-hydroxyquinoline and
a 4-quinolone structure, respectively. Tautomers B and C contain
an exocyclic double bond. Only the Z-configured geometric
isomers are considered because they contain an intramolecular
hydrogen bond N–H ◊ ◊ ◊ O and are expected to be more stable than
the corresponding E-configured isomers.
derivatives and was thus chosen for the NMR experiments. Due to
solubility reasons, all experiments had to be carried out in DMSO.
Therefore, low temperature experiments could not be carried
out. Most signals are strongly temperature- and concentration-
dependent. They are broad because of the intra- or intermolecular
chemical exchange among the tautomers. Even in DMSO, no well-
resolved or at least reasonably sharp signals were found for the
“active” protons (OH or NH). Several 13C NMR signals, which
suffered broadening as well, sharpened a little bit upon warming
The tautomerism was studied by NMR spectroscopy and by
computational methods. The NMR studies are hampered by the
low solubility of products 8 in most organic solvents and in water.
Derivative 8f showed the best, albeit still poor, solubility of all
◦
of the solution to 50 C. Despite these problems, it was possible
to carry out shift correlation experiments which allowed to assign
the signals of most of the atomic positions.
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Table 2 Synthesis of 4-hydroxyquinolines 8a–g
Table 3 Computed relative energies (DH/kcal mol-1)
Method
A
B
C
D
B3LYPa,b
4.89
(4.28)
0.46
5.08
-0.61
3.11
4.17
0.00
(3.55)
6.91
5.43
8.31
(3.77)
6.71
5.21
8.21
(0.00)
0.00
0.00
0.00
MP2c
B3LYP-IPCM/DMSOd
MP2-IPCM/DMSOe
a At B3LYP/6–311+G** (full optimization). b The Gibbs free energies
(corrected at 298 K) in parenthesis. c Single-point energy at B3LYP/
6–311+G**//B3LYP/6–311+G**. d Single-point energy with DMSO
as solvent at B3LYP/6–311+G**-IPCM//B3LYP/6–311+G**. e Single-
point energy with DMSO as solvent at MP/6–311+G**-IPCM/B3LYP/
6–311+G**.
MP2/6–311+G**, isomers D and A are most stable and in close
energy, while B and C are higher in energy.
Since all NMR data have been detected in DMSO, we have
calculated the relative energies by using DMSO as solvent and
an isodensity surface polarized continuum model (IPCM). At
B3LYP-IPCM, D is most stable in DMSO, followed by A. At
MP2-IPCM, A becomes most stable, closely followed by D, while
B and C are higher in energy (Table 3).
On the basis of the calculated energies and the NMR parame-
ters, it is to conclude that isomers A and D are the most dominant
resonance structures (rapid equilibrium). Tautomer B might be
present in small quantity, and C can be ruled out.
The condensation of the dianion of 2-acetylphenol (10), with
dimethyl pentane-1,5-dioate (11) afforded product 12 which is
structurally related to 3a (Scheme 2). The reaction of 12 with
boron tribromide resulted, following the conditions of the trans-
formation of 3a into 5a, in the formation of chromone 13 in 68%
yield. In addition, a small amount of the starting material 12 (14%)
was recovered.
7,8
R1
R2
R3
% (7)a
% (8)a
a
b
c
d
e
f
H
H
OMe
Me
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
Cl
Me
F
60
62
94
68
58
63
58
67
69
0
86
37
86
68
g
a Yields of isolated products; 7a–g: keto/enol = 0 : 100.
The presence of CH2 protons next to the ester group shows
that tautomers A or D are predominantly present. However, the
resonance of quinoline carbon atom C-4 (attached to the oxygen)
could not be located, due to extreme broadening (coalescence).
Therefore, it remains unclear whether tautomer A or D is present.
The broadening of the signals suggests that there is a fast
equilibrium (on the NMR time scale). Only very small signals were
observed which are tentatively assigned to tautomer B (with some
1
uncertainty). In a H NOESY experiment, a chemical exchange
between the CH2 protons of A/D and water was detected. The
facile exchange might be explained by the presence of a small
amount of enamine tautomers B or C. The complex exchange
behaviour of compound 8f became obvious from exchanging the
acidic protons by D2O addition. Not only the broad resonance at
high frequency, but also the 1H and 13C signals assigned to the CH2
group disappeared. This facile exchange might be again explained
by the participation of a small amount of tautomer B or C. It is
worth to be noted that the signals of carbon atom C-3 remained
unaffected. This observation rules out a significant participation
of tautomer C.
To further clarify this problem we have carried out
computations15 at the B3LYP/6–311+G** and MP2/6–311+G**
levels of theory for getting the energetic order of the tautomeric
structures A–D. At first we have optimized A–D at the B3LYP/
6–311+G** level and they are found to energy minimums by
frequency calculations. For comparison we have carried out MP2/
6–311+G** single-point energy calculations on the B3LYP/
6–311+G** geometries. As given in Table 3, isomer D is most
stable at B3LYP/6–311+G**, while A–C are higher in energy. At
Scheme 2 Synthesis of chromone 13; i, (1) LDA (2.2 equiv.), THF, 0 ◦C,
1 h; (2) 10, -78 ◦C, 30 min; (3) 11 (1.0 equiv.), 78 → 10 ◦C, 12 h, HCl
(10%); ii, BBr3 (8.0 equiv.), CH2Cl2, 0 ◦C.
Conclusions
In conclusion, we reported the reaction of 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene with 2-methoxybenzoyl chlo-
rides to give 3,5-diketoesters which were transformed, by treatment
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with boron tribromide, into functionalized 2-hydroxychroman-
4-ones or chromones. The reaction of 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene with 2-nitrobenzoyl chlo-
rides and subsequent hydrogenation afforded functionalized 4-
hydroxyquinolines. The tautomeric equilibrium of these molecules
was studied by NMR spectroscopy and by computational
methods.
keto/enol = 0 : 100): d = 1.39 (t, 3J = 6.97 Hz, 3H, OCH2CH3),
3
1.45 (t, J = 6.98 Hz, 3H, OCH2CH3), 3.47 (s, 2H, CH2), 3.99
3
(s, 3H, CH3), 4.02 (q, J = 6.98 Hz, 2H, OCH2CH3), 4.06 (q,
3
3J = 6.97 Hz, 2H, OCH2CH3), 6.76 (s, 1H, CH), 6.88 (d, J =
9.03 Hz, 1H, Ar), 6.99 (dd, 3J = 9.00 Hz, 4J = 3.18 Hz, 1H, Ar),
4
7.47 (d, J = 3.15 Hz, 1H, Ar), 15.82 (s, 1H, OH). 13C NMR
(75 MHz, CDCl3): d = 15.2 (CH3), 46.4 (CH2), 52.7 (CH3), 64.4,
65.3 (CH2), 102.1 (CH), 114.6, 114.9, 120.8 (Ar), 123.8, 152.9,
-1
˜
153.1 (C), 168.4, 180.3, 190.1 (CO). IR (KBr, cm ): n = 3452 (w),
Experimental section
3151 (w),3094 (w), 2981 (m), 2936 (m), 2885 (m), 1741 (s), 1575 (s,
br), 1503 (s), 1474 (s), 1438 (m), 1396 (s), 1250 (s), 1218 (s), 1148
(m), 1112 (s), 1049 (s), 1012 (m), 967 (w), 926 (m), 888 (w), 857
(w), 814 (m), 801 (m), 776 (w), 751 (m). MS (EI, 70 eV) m/z =
308 (M+, 5.9), 293 (18.2), 250 (21.3), 193 (100), 165 (28.5), 137
(19.5), 109 (11.6), 69 (10.2). Anal. calcd. for C16H20O6 (308.33): C,
62.33; H, 6.54. Found: C, 62.16; H, 6.48.
General Comments
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 (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O) or electrospray ionization
(ESI). For preparative scale chromatography, silica gel (60–
200 mesh) was used. Melting points are uncorrected.
Methyl 3,5-dioxo-5-(2-methoxy-5-chlorophenyl)pentanoate (3c).
Starting with 2c (1.100 g, 5.4 mmol) dissolved in CH2Cl2 (10 mL)
and 1 (3.000 g, 11.5 mmol), 3c was isolated as an orange solid
(1.280 g, 84%); mp 64–66 ◦C. 1H NMR (300 MHz, CDCl3,
keto/enol = 0 : 100): d = 3.48 (s, 2H, CH2), 3.75 (s, 3H, CH3), 3.89
(s, 3H, CH3), 6.57 (s, 1H, CH), 6.89 (d, 3J = 8.91 Hz, 1H, Ar), 7.37
(dd, 3J = 8.88 Hz, 4J = 2.73 Hz, 1H, Ar), 7.85 (d, 4J = 2.73 Hz,
1H, Ar), 15.69 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): d = 46.2
(CH2), 52.7, 56.3 (CH3), 102.2 (CH), 113.3 (Ar), 124.5, 126.3 (C),
General procedure for the synthesis of 3,5-dioxoalkanoates 3a–e
and 7a–g
To a CH2Cl2 solution of 1 (2.0 equiv.) was slowly added the acid
◦
chloride (1.0 equiv.) at -78 C. The reaction mixture was slowly
warmed to 20 ◦C during 6 h and the solution was stirred at 20 ◦C
for a further 6–8 h. To the solution was added a saturated aqueous
solution of NaHCO3 (20 mL). The organic and the aqueous layer
were separated and the latter was extracted with CH2Cl2 (3 ¥
10 mL). The combined organic layers were dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, n-heptane/EtOAc = 2 : 1)
to give the respective products.
130.1, 133.1 (Ar), 157.4 (C), 168.3, 178.9, 190.5 (CO). IR (KBr,
-1
˜
cm ): n = 3452 (m), 3148 (m), 3092 (m), 3033 (w), 2977 (w), 2957
(m), 2848 (m), 1735 (s), 1694 (w), 1609 (s), 1564 (s), 1492 (s), 1457
(s), 1438 (s), 1413 (m), 1327 (s), 1273 (s), 1251 (s), 1209 (s), 1172
(s), 1128 (s), 1113 (s), 1072 (s), 1020 (s), 1004 (m), 967 (m), 934
(w), 911 (m), 883 (m), 826 (s), 810 (s), 770 (m). MS (EI, 70 eV):
m/z (%) = 284 (M+, 7.8), 253 (28.3), 211 (12.4), 171 (29.7), 169
(100), 126 (9.6), 111 (8.3), 69 (11.0). Anal. calcd. for C13H13ClO5
(284.69): C, 54.84; H, 4.60. Found: C, 54.73; H, 4.73.
Methyl 3,5-dioxo-5-(2-methoxyphenyl)pentanoate (3a). Start-
ing with 2a (0.980 g, 5.8 mmol) and 1 (3.00 g, 11.5 mmol), dissolved
in CH2Cl2 (10 mL), 3a was isolated as a yellow oil (0.650 g, 45%).
1H NMR (300 MHz, CDCl3, keto/enol = 14 : 86): keto: d =
3.62 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.91 (s, 3H, ArOCH3),
4.21 (s, 2H, CH2), 6.99 (d, 3J = 8.4 Hz, 1H, Ar), 7.03 (ddd, 3J =
7.3 Hz, 3J = 8.8 Hz, 4J = 1.0 Hz, 1H, Ar), 7.52 (ddd, 3J = 8.8 Hz,
Methyl 3,5-dioxo-5-(2-methoxy-4-chlorophenyl)pentanoate (3d).
Starting with 2d (1.180 g, 5.7 mmol) dissolved in CH2Cl2 (10 mL)
and 1 (3.000 g, 11.5 mmol), 3d was isolated as an orange solid
(1.380 g, 85%); mp 37–38 ◦C. 1H NMR (300 MHz, CDCl3,
keto/enol = 0 : 100): d = 3.47 (s, 2H, CH2), 3.74 (s, 3H, CH3), 3.91
(s, 3H, CH3), 6.56 (s, 1H, CH), 6.96 (d, 4J = 1.98 Hz, 1H, Ar), 7.02
(dd, 3J = 8.46 Hz, 4J = 1.98 Hz, 1H, Ar), 7.87 (d, 3J = 8.46 Hz,
1H, Ar), 15.79 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): d = 46.3
(CH2), 52.7, 56.3 (CH3), 102.0 (CH), 112.6, 121.4 (Ar), 121.9 (C),
4
3
4
3J = 7.3 Hz, J = 1.0 Hz, 1H, Ar), 7.86 (dd, J = 7.8 Hz, J =
1.8 Hz, 1H, Ar); enol: 3.49 (s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.92
3
(s, 3H, ArOCH3), 6.59 (s, 1H, CH), 6.98 (d, J = 8.4 Hz, 1H,
3
3
4
Ar), 7.04 (ddd, J = 7.3 Hz, J = 8.8 Hz, J = 1.0 Hz, 1H, Ar),
3
3
4
7.47 (ddd, J = 8.8 Hz, J = 7.3 Hz, J = 1.0 Hz, 1H, Ar), 7.91
(dd, J = 7.8 Hz, J = 1.8 Hz, 1H, Ar), 15.82 (s, 1H, OH). 13C
NMR (75 MHz, CDCl3): enol: d = 46.3 (CH2), 52.8 (OCH3), 55.9
(OCH3), 102.1 (CH), 111.9, 121.1 (CHAr), 123.4 (CAr), 131.2,
3
4
131.7 (Ar), 139.5, 159.4 (C), 168.4, 179.5, 190.3 (CO). IR (KBr,
-1
˜
cm ): n = 3443 (w), 3149 (w), 3098 (w), 2980 (w), 2854 (w), 1728
(s), 1597 (s), 1571 (s), 1485 (s), 1472 (m), 1436 (s), 1414 (m), 1397
(m), 1344 (s), 1288 (m), 1243 (s), 1219 (s), 1176 (s), 1153 (m), 1135
(m), 1110 (m), 1068 (m), 1020 (s), 997 (m), 960 (m), 906 (w), 887
(s), 845 (w), 833 (s), 803 (s), 764 (m). MS (CI, isobutane): m/z
(%) = 285 ([M+H]+, 100). Anal. calcd. for C13H13ClO5 (284.69):
C, 54.84; H, 4.60. Found: C, 54.48; H, 4.27.
133.8 (CHAr), 159.0 (CAr), 168.5, 180.8, 190.1 (CO). IR (neat,
-1
˜
cm ): n = 3463 (w), 3078 (w), 2952 (m), 2842 (m), 2362 (w), 1744
(s), 1606 (s), 1491 (s), 1457 (s), 1437 (s), 1328 (m), 1250 (s), 1164
(m), 1074 (m), 1020 (m), 955 (w), 856 (w), 797 (w), 764 (m). MS
(EI, 70 eV): m/z (%) = 250 (M+, 13), 219 (24), 177 (14), 135 (100),
77 (12). HRMS (EI, 70 eV): calcd. for C13H14O5 (M+) 250.0836,
found 250.0828.
Methyl 3,5-dioxo-5-(3-ethoxynaphth-2-yl)pentanoate (3e).
Starting with 2e (1.340 g, 5.7 mmol) dissolved in CH2Cl2 (10 mL)
and 1 (3.000 g, 11.5 mmol), 3e was isolated as a yellow solid
(0.640 g, 36%); mp 46–48 ◦C. 1H NMR (300 MHz, CDCl3,
keto/enol = 0 : 100): d = 1.42 (t, 3J = 6.99 Hz, 3H, OCH2CH3),
Methyl
3,5-dioxo-5-(2,5-diethoxyphenyl)pentanoate
(3b).
Starting with 2b (1.200 g, 5.3 mmol) dissolved in CH2Cl2 (10 mL)
and 1 (3.000 g, 11.5 mmol), 3b was isolated as a yellow solid
(0.890 g, 55%); mp 37–38 ◦C. 1H NMR (300 MHz, CDCl3,
3
3.47 (s, 2H, CH2), 3.77 (s, 3H, CH3), 4.20 (q, J = 6.97 Hz, 2H,
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OCH2CH3), 5.99 (s, 1H, CH), 7.21–7.96 (m, 6H, Ar), 15.44 (s,
1H, OH). 13C NMR (75 MHz, CDCl3): d = 15.3 (CH3), 45.4
(CH2), 52.8 (CH3), 65.8 (CH2), 105.2 (CH), 114.9 (Ar), 120.5 (C),
(s), 757 (m, br). HRMS (ESI): calcd. for NaC13H13NO7 ([M+Na]+)
318.05842, found 318.05826. Anal. calcd. for C13H13NO7 (295.24):
C, 52.88; H, 4.44; N, 4.74. Found: C, 52.70; H, 4.61; N, 4.35.
124.5, 127.9, 128.4 (Ar), 129.1, 131.8 (C), 132.4 (Ar), 154.4 (C),
Methyl 3,5-dioxo-5-(3-methyl-2-nitrophenyl)pentanoate (7d).
The reaction was carried out following the procedure as given for
the synthesis of 5a. Starting with 6d (1.150 g, 5.8 mmol), CH2Cl2
(10 mL) and 1 (3.000 g, 11.5 mmol), 7d was isolated as a yellow
-1
˜
168.3, 186.4, 187.0 (CO). IR (KBr, cm ): n = 3397 (w), 2982 (m),
2952 (w), 2894 (w), 1745 (s), 1623 (s), 1596 (s), 1511 (s), 1465 (m),
1435 (s), 1375 (m), 1338 (m), 1277 (s), 1249 (s), 1150 (s), 1114 (m),
1091 (m), 1063 (s), 1025 (m), 966 (w), 861 (w), 809 (m), 751 (m).
MS (EI, 70 eV) m/z = 314 (M+, 39.2), 282 (10.3), 269 (42.8), 241
(11.7), 213 (20.3), 199 (100), 171 (89.2), 149 (10.8), 142 (17.8),
127 (13.2), 115 (33.8), 69 (9.3). HRMS (EI, 70 eV): calcd. for
C18H18O5 (M+) 314.1149, found 314.1148.
1
oil (1.100 g, 68%). H NMR (300 MHz, CDCl3, keto/enol = 0 :
100): d = 2.37 (s, 3H, CH3), 3.46 (s, 2H, CH2), 3.77 (s, 3H, CH3),
6.09 (s, 1H, CH), 7.45–7.54 (m, 3H, Ar), 15.11 (s, 1H, OH). 13C
NMR (75 MHz, CDCl3): d = 17.4 (CH3), 44.5 (CH2), 52.6 (CH3),
99.4 (CH), 126.8 (Ar), 128.9 (C), 130.2 (Ar), 131.2 (C), 134.8 (Ar),
-1
˜
167.6, 183.4, 186.6 (CO). IR (ATR, cm ): n = 2955 (w), 1739 (m),
Methyl 3,5-dioxo-5-(2-nitrophenyl)pentanoate (7a). Starting
with 6a (1.070 g, 5.8 mmol), CH2Cl2 (10 mL) and 1 (3.000 g,
11.5 mmol), 7a was isolated as a brownish oil (0.910 g, 60%). 1H
NMR (300 MHz, CDCl3, keto/enol = 0 : 100): d = 3.46 (s, 2H,
CH2), 3.77 (s, 3H, CH3), 5.96 (s, 1H, CH), 7.57–7.71 (m, 3H, Ar),
7.93–7.96 (m, 1H, Ar), 14.91 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3): d = 44.2 (CH2), 52.6 (CH3), 100.5 (CH), 124.5, 129.3
1669 (w), 1600 (m, br), 1530 (s), 1463 (m, br), 1366 (m), 1262 (s, br),
1197 (m), 1154 (m), 1073 (w), 1014 (m), 948 (w), 921 (w), 852 (m),
828 (w), 785 (s). HRMS (ESI): calcd. for NaC13H13NO6 ([M+Na]+)
302.06351, found 302.06317. Anal. calcd. for C13H13NO6 (279.25):
C, 55.91; H, 4.69; N, 5.02. Found: C, 56.00; H, 4.67; N, 5.03.
Methyl 3,5-dioxo-5-(5-chloro-2-nitrophenyl)pentanoate (7e).
Starting with 6e (1.270 g, 5.8 mmol), CH2Cl2 (10 mL) and 1
(3.000 g, 11.5 mmol), 7e was isolated as an orange oil (1.000 g,
58%). 1H NMR (300 MHz, CDCl3, keto/enol = 0 : 100): d = 3.47
(s, 2H, CH2), 3.76 (s, 3H, CH3), 5.94 (s, 1H, CH), 7.54–7.60 (m,
(Ar), 131.1 (C), 131.5 (Ar), 132.0 (C), 133.0 (Ar), 167.6, 185.4,
-1
˜
185.5 (CO). IR (ATR, cm ): n = 2954 (w), 2361 (w), 1739 (m),
1595 (m, br), 1572 (m), 1526 (s), 1436 (m), 1407 (w), 1346 (s), 1307
(m), 1243 (m, br), 1146 (m), 1060 (m), 1012 (m), 951 (w, br), 854
(m), 784 (m), 756 (m). MS (EI, 70 eV) m/z = 264 (M+, 4.6), 205
(3.6), 177 (16.3), 159 (3.2), 150 (100), 135 (13.8), 134 (14.5), 119
(8.6), 104 (18.1), 78 (11.2), 76 (24.7), 69 (13.4). Anal. calcd. for
C12H11NO6 (265.22): C, 54.34; H, 4.18; N, 5.28. Found: C, 54.43;
H, 4.11; N, 5.28.
3
2H, Ar), 7.93 (d, J = 8.40 Hz, 1H, Ar), 14.29 (s, 1H, OH). 13C
NMR (75 MHz, CDCl3): d = 43.9 (CH2), 52.7 (CH3), 100.6 (CH),
126.0, 129.3, 131.4 (Ar), 133.7, 139.6, 145.8 (C), 167.6, 184.8, 185.3
-1
˜
(CO). IR (ATR, cm ): n = 3102 (w), 2955 (w), 1740 (m), 1609 (m,
br), 1566 (m), 1528 (s), 1437 (m), 1342 (s), 1300 (m), 1242 (m, br),
1149 (m), 1103 (m), 1060 (w), 1011 (w), 907 (s), 839 (m), 727 (s).
MS (EI, 70 eV) m/z = 298 (M+, 1.0), 268 (9.1), 255 (10.2), 253
(34.7), 226 (10.3), 184 (100), 170 (21.8), 138 (17.1), 126 (17.9), 110
(23.2), 101 (55.7), 76 (32.4), 69 (28.2). HRMS (ESI): calcd. for
NaC12H10ClNO6 ([M+Na]+) 322.00889, found 322.00825.
Methyl 3,5-dioxo-5-(4-chloro-2-nitrophenyl)pentanoate (7b).
Starting with 6b (1.270 g, 5.8 mmol), CH2Cl2 (10 mL) and 1
(3.000 g, 11.5 mmol), 7b was isolated as an orange oil (1.070 g,
1
62%). H NMR (300 MHz, CDCl3, keto/enol = 0 : 100): d =
3.46 (s, 2H, CH2), 3.77 (s, 3H, CH3), 5.94 (s, 1H, CH), 7.54 (d,
3
4
3J = 8.10 Hz, 1H, Ar), 7.65 (dd, J = 8.25 Hz, J = 1.74 Hz,
1H, Ar), 7.91 (d, 4J = 1.60 Hz, 1H, Ar), 14.82 (s, 1H, OH).
13C NMR (75 MHz, CDCl3): d = 44.2 (CH2), 52.7 (CH3), 100.3
Methyl 3,5-dioxo-5-(5-methyl-2-nitrophenyl)pentanoate (7f).
Starting with 6f (1.150 g, 5.8 mmol), CH2Cl2 (10 mL) and 1
(3.000 g, 11.5 mmol), 7f was isolated as a yellow oil (1.01 g, 63%).
1H NMR (300 MHz, CDCl3, keto/enol = 0 : 100): d = 2.47 (s, 3H,
CH3), 3.44 (s, 2H, CH2), 3.77 (s, 3H, CH3), 5.30 (s, 1H, CH), 7.34–
7.40 (m, 2H, Ar), 7.86–7.89 (m, 1H, Ar), 14.84 (s, 1H, OH). 13C
NMR (75 MHz, CDCl3): d = 21.4 (CH3), 44.1 (CH2), 52.6 (CH3),
(CH), 124.8 (Ar), 130.1 (C), 130.5, 133.0 (Ar), 137.6, 148.4 (C),
-1
˜
167.5, 184.4, 185.6 (CO). IR (ATR, cm ): n = 3090 (w, br), 2955
(w), 1738 (m), 1598 (m, br), 1534 (s), 1436 (m), 1348 (s), 1260
(s, br), 1153 (s), 1115 (m), 1094 (m), 1065 (m), 1010 (m), 937 (w,
br), 890 (s), 840 (m), 799 (m), 766 (m). HRMS (ESI): calcd. for
C12H10ClNO6 ([M+1]+) 300.02694, found 300.02663. Anal. calcd.
for C12H10ClNO6 (299.66): C, 48.10; H, 3.36; Cl, 11.83; N, 4.67.
Found: C, 48.33; H, 3.86; Cl, 11.37; N, 4.37.
100.6 (CH), 124.5 (C), 124.6, 129.8, 131.7 (Ar), 144.7, 145.4 (C),
-1
˜
167.8, 184.7, 186.8 (CO). IR (ATR, cm ): n = 3107 (w), 3067 (w),
2955 (w), 2852 (w), 1741 (m), 1587 (m), 1519 (s), 1436 (m), 1403
(w), 1342 (s), 1313 (m), 1250 (m), 1190 (m), 1154 (m), 1117 (m),
1056 (m), 1012 (m), 895 (w), 834 (s), 757 (m), 735 (s). MS (EI, 70
eV) m/z = 278 (M+, 3.3), 191 (3.2), 164 (100), 148 (4.7), 118 (5.6),
89 (7.1), 77 (4.3). Anal. calcd. for C13H13NO6 (279.25): C, 55.91;
H, 4.69; N, 5.02. Found: C, 55.57; H, 4.46; N, 5.49.
Methyl 3,5-dioxo-5-(3-methoxy-2-nitrophenyl)pentanoate (7c).
The reaction was carried out following the procedure as given for
the synthesis of 5a. Starting with 6c (1.240 g, 5.8 mmol), CH2Cl2
(10 mL) and 1 (3.000 g, 11.5 mmol), 7c was isolated as an orange
◦
1
solid (1.600 g, 94%); mp 87 C. H NMR (300 MHz, CDCl3,
keto/enol = 0 : 100): d = 3.45 (s, 2H, CH2), 3.75 (s, 3H, CH3),
3.89 (s, 3H, CH3), 6.11 (s, 1H, CH), 6.96–7.48 (m, 3H, Ar), 15.04
(s, 1H, OH). 13C NMR (75 MHz, CDCl3): d = 44.5 (CH2), 52.7,
(4-Oxo-4H-chromen-2-yl)acetic acid methyl ester (5a). To a
CH2Cl2 solution (8 mL) of 3a (0.200 g, 0.8 mmol) was dropwise
added BBr3 (0.800 g, 3.2 mmol) at 0 ◦C. The reaction mixture was
slowly warmed to 20 ◦C and was stirred for 6–8 h at this temper-
ature. The reaction was quenched by adding 30 mL of water. The
organic layer was separated and washed with water. The aqueous
layer was repeatedly extracted with CH2Cl2. The combined organic
layers were dried (sodium sulfate), filtered, and dried in vacuo.
The residue was purified by column chromatography (silica,
56.7 (CH3), 99.4 (CH), 116.3, 120.2 (Ar), 129.1 (C), 131.3 (Ar),
-1
˜
139.4, 151.2 (C), 167.6, 182.4, 187.0 (CO). IR (ATR, cm ): n =
3005 (w), 2955 (w), 2906 (w), 1734 (m), 1601 (m, br), 1575 (s), 15.35
(s), 1461 (s, br), 1373 (s), 1281 (s, br), 1207 (s), 1144 (s), 1044 (s),
1006 (m), 946 (m), 909 (m), 894 (w), 852 (s), 819 (w), 808 (w), 789
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n-heptane/EtOAc = 2 : 1) to give 5a as a colourless solid (0.130 g,
NMR (300 MHz, CDCl3): d = 2.80–3.13 (m, 4H, CH2), 3.84 (s,
◦
1
3
76%); mp 96 C. H NMR (300 MHz, CDCl3): d = 3.67 (s, 2H,
3H, CH3), 5.89 (s, 1H, OH), 7.07 (d, J = 8.97 Hz, 1H, Ar),
3
CH2), 3.78 (s, 3H, OCH3), 6.30 (s, 1H, CH), 7.37–7.46 (m, J =
7.40–7.96 (m, 4H, Ar), 9.28 (d, 3J = 8.01 Hz, 1H, Ar). 13C NMR
(75 MHz, CDCl3): d = 42.7, 49.0 (CH2), 52.8 (CH3), 100.5, 112.6
8.1 Hz, 2H, Ar), 7.66 (ddd, 3J = 6.9 Hz, 3J = 8.0 Hz, 4J = 1.7 Hz,
1H, Ar), 8.18 (dd, 3J = 8.0 Hz, 4J = 1.4 Hz, 1H, Ar). 13C NMR
(75 MHz, CDCl3): d = 40.4 (CH2), 53.0 (OCH3), 112.7 (CH), 118.3
(C), 119.3, 125.3, 126.2, 128.6 (Ar), 129.7 (C), 130.0 (Ar), 131.4
-1
˜
(C), 137.8 (Ar), 160.1 (C), 171.9, 191.6 (CO). IR (KBr, cm ): n =
(CHAr), 123.9 (CAr), 125.6, 126.0, 134.1 (CHAr), 156.8 (CAr),
3406 (m), 2956 (w), 1711 (s), 1674 (s), 1618 (m), 1597 (m), 1572
(w), 1513 (m), 1463 (m), 1440 (s), 1407 (m), 1370 (m), 1347 (m),
1282 (w), 1265 (w), 1232 (s), 1209 (s), 1178 (m), 1157 (s), 1123 (m),
1083 (w), 1027 (w), 1008 (s), 986 (w), 964 (w), 921 (w), 878 (m),
863 (w), 829 (s), 789 (w), 762 (m). MS (EI, 70 eV): m/z = 286 (M+,
19.2), 268 (16.9), 254 (18.4), 213 (36.2), 181 (15.4), 171 (100), 142
(30.9), 114 (45.4), 89 (9.3), 77 (10.8), 69 (14.2). HRMS (EI, 70 eV):
calcd. for C16H14O5 (M+) 286.0836, found 286.0830.
-1
˜
161.4, 168.1, 178.3 (CO). IR (KBr, cm ): n = 3450 (m), 3064 (w),
3006 (w), 2955 (m), 2932 (m), 1985 (w), 1951 (w), 1731 (s), 1644
(s), 1609 (s), 1572 (m), 1475 (m), 1465 (m), 1438 (m), 1416 (m),
1397 (s), 1344 (s), 1307 (m), 1251 (m), 1204 (s), 1165 (s), 1122 (m),
1024 (w), 995 (m), 969 (m), 953 (m), 907 (m), 871 (m), 848 (m),
785 (m), 758 (s), 740 (m). MS (CI, isobutane): m/z (%) = 219
([M+isobutane]+, 13). HRMS (CI): calcd. for C12H11O4 ([M+1]+)
219.0652, found 219.0649. Anal. calcd. for C12H10O4 (218.12): C,
66.08; H, 4.62. Found C, 66.11; H, 4.60.
General procedure for the synthesis of quinolines 8a–g
A MeOH solution of 7a–g and of Pd/C was stirred under a
hydrogen atmosphere for 24 h at 20 ◦C. The catalyst was filtered
off and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, EtOAc/heptanes).
(6-Chloro-4-oxo-4H-chromen-2-yl)acetic acid methyl ester (5c).
The reaction was carried out following the procedure as given
for the synthesis of 5a. Starting with 3c (0.230 g, 0.8 mmol),
CH2Cl2 (8 mL), and BBr3 (0.31 mL, 3.2 mmol), 5c was isolated as a
colorless solid (0.150 g, 73%); mp 90–93 ◦C. 1H NMR (300 MHz,
CDCl3): d = 3.67 (s, 2H, CH2), 3.78 (s, 3H, CH3), 6.31 (s, 1H,
Methyl 2-(4-hydroxyquinolin-2-yl)acetate (8a). Starting with
7a (0.200 g, 0.8 mmol), MeOH (3 mL) and Pd/C (10 mol%), 8a
3
3
CH), 7.33 (d, J = 8.94 Hz, 1H, Ar), 7.61 (dd, J = 8.91 Hz,
4J = 2.61 Hz, 1H, Ar), 8.15 (d, 4J = 2.58 Hz, 1H, Ar). 13C NMR
(75 MHz, CDCl3): d = 40.3 (CH2), 53.2 (CH3), 112.7 (CH), 120.1
◦
1
was isolated as a pale grey solid (0.110 g, 67%); mp 179 C. H
NMR (300 MHz, DMSO-d6): d = 3.67 (s, 3H, CH3), 3.90 (s, 2H,
CH2), 6.11 (s, 1H, CH), 7.43 (m, 1H, Ar), 7.76 (m, 1H, Ar), 7.87 (m,
1H, Ar), 8.10 (m, 1H, Ar), 11.85 (s, 1H, OH). 13C NMR (75 MHz,
DMSO-d6): d = 37.2 (CH2), 52.1 (CH3), 108.7 (CH), 115.3, 124.3
(Ar), 124.9 (C), 125.5 (Ar), 131.6 (C), 134.3 (Ar), 155.1, 161.7 (C),
-1
˜
168.0, 177.1 (CO). IR (KBr, cm ): n = 3421 (s, br), 3123 (w), 3065
(m), 2999 (w), 2955 (w), 1747 (s), 1698 (w), 1654 (s), 1610 (s), 1572
(m), 1473 (m), 1450 (s), 1400 (m), 1380 (m), 1332 (m), 1268 (m),
1198 (s), 1177 (s), 1156 (s), 1137 (m), 1105 (m), 1070 (w), 1001 (m),
959 (m), 942 (w), 903 (w), 864 (m), 846 (m), 801 (m), 775 (w), 740
(m). MS (EI, 70 eV) m/z = 252 (M+, 100), 208 (22.0), 165 (55.5),
126 (15.5), 102 (11.4). HRMS (EI, 70 eV): calcd. for C12H9O4Cl
(M+) 252.0184, found 252.0181.
(C), 124.7, 124.8, 131.9, 132.0 (Ar), 140.8 (CO), 145.7 (C), 169.0
-1
˜
(CO). IR (ATR, cm ): n = 3100 (w), 3075 (w), 2988 (w), 2959 (w),
1733 (s), 1594 (m, br), 1547 (m, br), 1454 (m), 1430 (m), 1407 (m),
1342 (s), 1247 (m, br), 1212 (m, br), 1166 (s), 1150 (s), 985 (s, br),
899 (s), 829 (s), 779 (s), 751 (s). MS (EI, 70 eV) m/z = 217 (M+,
34.0), 201 (100), 185 (14.2), 173 (11.7), 159 (43.7), 157 (17.8), 145
(14.6), 129 (46.1), 102 (18.4), 77 (13.7), 67 (19.1). HRMS (EI,
70 eV): calcd. for C12H11NO3 (M+) 217.0733, found 217.0739.
(7-Chloro-2-hydroxy-4-oxo-4H-chroman-2-yl)acetic acid methyl
ester (4d). The reaction was carried out following the procedure
as given for the synthesis of 5a. Starting with 2d (0.230 g,
0.8 mmol), CH2Cl2 (8 mL) and BBr3 (0.31 mL, 3.2 mm◦ol), 8d
Methyl 2-(7-chloro-4-hydroxyquinolin-2-yl)acetate (8b). Start-
ing with 7b (0.230 g, 0.8 mmol), MeOH (3 mL) and Pd/C
(10 mol%), 8b was isolated as a pale grey solid (0.13 g, 69%);
1
◦
1
was isolated as a colorless solid (0.08 g, 37%); mp 72–74 C. H
mp 204 C. H NMR (300 MHz, DMSO-d6): d = 3.67 (s, 3H,
CH3), 3.93 (s, 2H, CH2), 6.20 (s, 1H, CH), 7.45 (d, 3J = 8.61 Hz,
1H, Ar), 7.87 (s, 1H, Ar), 8.11 (d, 3J = 8.64 Hz, 1H, Ar), 12.03 (s,
1H, OH). 13C NMR (75 MHz, DMSO-d6): d = 37.0 (CH2), 52.1
NMR (300 MHz, CDCl3): d = 2.77–3.07 (m, 4H, CH2), 3.84 (s,
3H, CH3), 5.94 (s, 1H, OH), 6.98–7.04 (m, 2H, Ar), 7.83 (d, 3J =
8.34 Hz, 1H, Ar). 13C NMR (75 MHz, CDCl3): d = 42.8, 47.5
(CH2), 52.9 (CH3), 101.0 (C), 118.9 (Ar), 119.7 (C), 122.9, 128.0
(CH3), 109.3 (CH), 114.4 (Ar), 123.0 (C), 124.1, 127.2 (Ar), 137.0
-1
-1
˜
(Ar), 142.2, 158.5 (C), 176.9, 195.5 (CO). IR (KBr, cm ): n = 3369
˜
(CCl), 140.6 (CO), 146.8 (C), 168.7 (CO). IR (ATR, cm ): n =
(s, br), 3005 (w), 2952 (w), 2922 (w), 1733 (s),1685 (s), 1647 (w),
1603 (w), 1569 (m), 1495 (w), 1475 (w), 1459 (w), 1425 (m), 1352
(m), 1318 (m), 1306 (m), 1288 (w), 1217 (s), 1179 (w), 1147 (m),
1118 (w), 1099 (m), 1079 (m), 1062 (w), 1003 (m), 950 (m), 923 (m),
901 (w), 866 (m), 831 (w), 822 (m), 779 (w), 742 (w), 725 (w). MS
(EI, 70 eV) m/z = 270 (M+, 13.5), 238 (8.4), 199 (38.4), 197 (98.0),
157 (38.2), 155 (100), 126 (13.4), 99 (11.1), 69 (17.5). HRMS (EI,
70 eV): calcd. for C12H11O5Cl (M+) 270.0290, found 270.0288.
3097 (w), 3010 (w), 2956 (w), 2845 (w), 2113 (w, br), 1731 (s), 1594
(m, br), 1546 (m, br), 1437 (m), 1405 (m), 1340 (s), 1237 (m, br),
1142 (s), 976 (s), 903 (s), 843 (s), 821 (s), 755 (s). MS (EI, 70 eV)
m/z = 251 (M+, 28.7), 237 (16.9), 235 (47.3), 219 (13.1), 207 (15.4),
195 (25.5), 193 (76.9), 179 (18.9), 164 (46.1), 128 (16.9), 105 (10.6),
101 (13.6), 91 (11.5), 75 (15.9), 69 (38.9). HRMS (ESI): calcd. for
C12H11ClNO3 ([M+H]+) 252.0422, found 252.0416.
Methyl
2-(4-hydroxy-8-methylquinolin-2-yl)acetate
(8d).
Methyl 2-(3-hydroxy-1-oxo-2,3-dihydro-1H-benzo[f ]-chromen-
3-yl)acetate (4e). The reaction was carried out following the
procedure as given for the synthesis of 5a. Starting with 2e (0.250 g,
0.8 mmol), CH2Cl2 (8 mL) and BBr3 (0.3 mL, 3.2 mmol), ◦4e was
Starting with 7d (0.210 g, 0.8 mmol), MeOH (3 mL) and Pd/C
(10 mol%), 8d was isolated as a pale green solid (0.150 g, 86%);
mp 221 C. H NMR (300 MHz, DMSO-d6): d = 2.50 (s, 3H,
CH3), 3.67, 3.68 (s, 3H, CH3), 3.87, 3.89 (s, 2H, CH2), 6.03, 6.04
(s, 1H, CH), 7.23 (dd, 3J = 7.62 Hz, 3J = 7.59 Hz, 1H, Ar), 7.49
◦
1
1
isolated as a colorless solid (0.120 g, 53%); mp 120–122 C. H
1936 | Org. Biomol. Chem., 2009, 7, 1931–1938
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3
4
(m, 1H, Ar), 7.94, 8.02 (dd, J = 7.60 Hz, J = 1.56 Hz, 1H,
Ar), 10.59, 11.58 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6):
d = 17.6 (CH3), 37.7, 38.4 (CH2), 52.0 (CH3), 110.3 (CH),
7-(2¢-Hydroxyphenyl)-5,7-dioxoheptanoic acid methyl ester (12).
To a THF solution of LDA (44.0 mmol) was added 10 (2.72 g,
20.0 mmol) at -78 ◦C. After stirring for 1 h, 11 (3.20 g, 20.0 mmol)
was dropwise added. The solution was allowed to slowly warm
to 10 ◦C during 12 h. To the solution was added hydrochloric
acid (20 mL, 10%) and the organic and the aqueous layer were
separated. The latter was extracted with ether (5 ¥ 40 mL). The
combined organic layers were dried (sodium sulfate), filtered and
the filtrate was concentrated in vacuo. The residue w purified by
chromatography (silica gel, hexanes/EtOAc = 10 : 1 → 1 : 1)
122.7, 122.8 (Ar), 124.9, 126.1 (C), 132.6 (Ar), 138.8, 146.0 (C),
-1
˜
169.1, 169.6, 177.1 (CO). IR (ATR, cm ): n = 3253 (w), 3172
(w), 3114 (w), 3068 (w), 2988 (w), 2950 (w), 1732 (s), 1628 (w),
1610 (m), 1599 (m), 1563 (s), 1519 (m, br), 1421 (s), 1344 (s),
1310 (m), 1248 (m, br), 1200 (s), 1168 (s), 1072 (m), 1006 (m),
989 (m), 899 (m, br), 848 (m), 804 (s), 751 (s). MS (EI, 70 eV)
m/z = 231 (M+, 100), 199 (14.4), 171 (72.4), 143 (76.3), 115 (9.9).
HRMS (EI, 70 eV): calcd. for C13H13NO3 (M+) 231.08899, found
231.08879.
1
to give 12 (2.90 g, 56%) as a yellow oil. H NMR (300 MHz,
CDCl3, enol): d = 1.99–2.05 (m, 2 H, CH2), 2.36 (m, 4 H, CH2),
3.69 (s, 3 H, OCH3), 6.18 (s, 1 H, Enol-CH), 6.85–7.01 (m, 2 H,
Ar), 7.47 (m, 1 H, Ar), 7.65 (m, 1 H, Ar), 12.02 (s, 1 H, enol-
OH), 14.97 (s, 1 H, Ar-OH). 13C NMR (DEPT, CDCl3, 75.5 MHz,
enol): d = 21.5 (CH2CH2CH2), 33.0, 35.4 (CH2), 51.6 (CH3), 95.0
Methyl 2-(6-chloro-4-hydroxyquinolin-2-yl)acetate (8e). Start-
ing with 7e (0.230 g, 0.8 mmol), MeOH (3 mL) and Pd/C
(10 mol%), 8e was isolated as a yellow solid (0.070 g, 37%); mp
218 ◦C. 1H NMR (300 MHz, DMSO-d6): d = 3.61 (s, 3H, CH3),
3.90 (s, 2H, CH2), 6.22 (s, 1H, CH), 7.62–7.90 (m, 2H, Ar), 8.04
(s, 1H, Ar), 12.34 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6):
d = 37.0 (CH2), 52.2 (CH3), 109.1 (CH), 118.0, 123.6 (Ar), 125.5,
(enol-CH), 118.7, 119.0, 128.5 (ArCH), 130.7 (C), 135.8 (ArCH),
-1
˜
162.5, 173.3, 184.7, 195.6 (C). IR (neat, cm ): n = 3422 (m), 2953
(m), 1736 (s), 1693 (s), 1610 (s), 1579 (s), 1488 (s), 1440 (s), 1367
(m), 1301 (s), 1213 (s), 1157 (s), 1114 (m), 1029 (m), 895 (m), 815
(w), 762 (m). UV-VIS (CH3CN, nm): lmax (log e): 314 (3.83), 251
(3.94), 212 (4.37). MS (EI, 70 eV): m/z (%) = 264 (M+, 21), 233
([M-OCH3]+, 12), 163 ([M-C5H9O2]+, 98), 121 ([M-C7H11O3]+,
100), 101 (21). HRMS (FT-ICR): calcd. for C14H17O5 ([M+1]+):
265.10705; found: 265.10738.
128.6 (C), 131.9 (Ar), 138.7 (CCl), 146.5, 168.8 (CO). IR (ATR,
-1
˜
cm ): n = 3096 (w), 3011 (w), 2953 (w), 2849 (w), 1737 (m), 1594
(m, br), 1564 (m), 1528 (m), 1436 (m), 1341 (s), 1299 (m), 1251
(m, br), 1199 (m), 1170 (m), 1102 (m), 1009 (m), 933 (m), 886 (m),
818 (s), 756 (s). HRMS (ESI): calcd. for C12H11ClNO3 ([M+H]+)
252.0422, found 252.0422.
4-(Chromon-2¢-yl)butanoic acid methyl ester (13). To a CH2Cl2
solution (30 mL) of 12 (630 mg, 2.4 mmol) was slowly added
BBr3 (2.390 g, 10.0 mmol) at 0 ◦C. The temperature was allowed
to slowly rise to 20 ◦C during 12 h with stirring. Hydrochloric
acid (5%) was added and the organic and aqueous layers were
separated. The latter was extracted with CH2Cl2 (4 ¥ 10 mL). The
combined organic layers were dried (sodium sulfate), filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, hexanes/EtOAc = 5 : 1 → 1 : 3) to give
13 (398 mg, 68%) as a yellow solid and recovered starting material
Methyl 2-(4-hydroxy-6-methylquinolin-2-yl)acetate (8f). Start-
ing with 7f (0.210 g, 0.8 mmol), MeOH (3 mL) and Pd/C
(10 mol%), 8f was isolated as a yellow solid (0.150 g, 86%); mp
172 ◦C. 1H NMR (300 MHz, 298 K, DMSO-d6): d = 2.44 (s, 3H, 6-
CH3), 3.64 (s, 3H, OCH3), 3.89 (s, 2H, CH2), 6.25 (s, 1H, 3-H), 7.57
(dd, 3J= 3.6 Hz, 4J= 1.7 Hz, 1H, 7-H), 7.85 (d, 3J= 8.6 Hz, 1H,
8-H), 7.91 (br, 1H, 5-H), 11.6 (very broad, OH/NH). 13C NMR
(75 MHz, 298 K, DMSO-d6): d = 20.7 (6-CH3), 37.2 (CH2), 52.0
(OCH3), 108.0 (C3), 115.9 (C8), 123.7 (C5), 124.2 (C4a), 133.2
◦
1
(C7), 133.8 (C6), 138.5 (C8a), 145.0 (C2), 169.0 (CO). IR (ATR,
12 (89 mg, 14%); mp 121 C. H NMR (300 MHz, CDCl3): d =
-1
3
˜
cm ): n = 2953 (w), 2921 (w), 2850 (w), 1731 (m), 1591 (m, br),
=
2.12 (m, 2 H, CH2CH2CH2), 2.45 (t, J = 7.3 Hz, 2 H, CH2C CH),
3
1561 (m, br), 1434 (m), 1336 (s), 1249 (s, br), 1168 (s, br), 1009 (s,
br), 818 (s), 760 (s). HRMS (ESI): calcd. for C13H14NO3 ([M+H]+)
232.09682, found 232.09677.
2.70 (t, J = 7.4 Hz, 2 H, CH2COOCH3), 3.69 (s, 3 H, OCH3),
6.19 (s, 1 H, CH), 7.36 - 7.44 (m, 2 H, Ar), 7.65 (m, 1 H, Ar),
8.17 (d, 3J = 8.1 Hz, J = 1.7 Hz, 1 H, Ar). 13C NMR (DEPT,
4
75.5 MHz, CDCl3): d = 21.9 (CH2CH2CH2), 32.8, 33.4 (CH2),
Methyl 2-(6-fluoro-4-hydroxyquinolin-2-yl)acetate (8g). Start-
ing with 7g (0.210 g, 0.8 mmol), MeOH (3 mL) and Pd/C
(10 mol%), 8g was isolated as a yellow solid (0.12 g, 68%); mp
51.6 (OCH3), 110.1 (CH), 117.8 (ArCH), 123.6 (C), 124.9, 125.6,
=
=
133.5 (ArCH), 156.4, 168.3 (C), 173.0 (C O, ester), 178.1 (C O,
-1
˜
ketone). IR (KBr, cm ): n = 3446 (m), 2952 (m), 1738 (s), 1654 (s),
◦
1
>310 C. H NMR (300 MHz, DMSO): d = 3.63 (s, 3H, CH3),
3.88 (s, 2H, CH2), 6.23 (s, 1H, CH), 7.54–7.60 (m, 1H, Ar), 7.75
(dd, 3J = 9.21 Hz, 4J = 2.79 Hz, 1H, Ar), 7.95 (dd, 3J = 9.27 Hz,
3J = 9.27 Hz, 1H, Ar). 13C NMR (75 MHz, DMSO-d6): d = 37.1
(CH2), 51.9 (CH3), 108.0 (CH), 108.6 (d, 2J = 22.7 Hz, Ar), 118.9
1609 (s), 1574 (m), 1464 (s), 1434 (m), 1386 (s), 1342 (s), 1251 (m),
1214 (s), 1204 (s), 1155 (m), 1119 (w), 963 (m), 840 (w), 784 (m),
759 (m). UV-VIS (CH3CN, nm): lmax (log e): 302 (3.76), 292 (3.76),
260 (3.72), 251 (3.76), 227 (3.94). MS (EI, 70 eV): m/z (%) = 246
(M+, 18), 215 (12), 187 (5), 173 (10), 160 (5), 121 (15), 92 (11), 55
(15). Anal. calcd. for C14H14O4 (246): C 68.28 H 5.73. Found: C
67.95, H 5.72.
3
2
3
(d, J = 8.5 Hz, Ar), 120.3 (d, J = 26.4 Hz, Ar), 125.7 (d, J =
8.4 Hz, C), 137.0 (C), 145.7 (CO), 158.4 (d, 1J = 243.4 Hz, CF),
168.9 (CO).19F NMR (282 MHz, DMSO-d6): d = -116.92 (CF).
-1
˜
IR (ATR, cm ): n = 3114 (w), 3081 (w), 2957 (w), 1733 (m), 1599
Computed energetic data. (a) B3LYP/6–311+G** (full optimi-
zation) total energies (au): A (-783.88149); B (-783.88433); C
(-783.88264); D (-783.88929). (b) B3LYP/6–311+G** Gibbs
energies (au, corrected at 298 K): A (-783.68893); B (-783.69008);
C (-783.68974); D (-783.69575). (c) MP2/6–311+G**//B3LYP/
6–311+G** total energies (au): A (-781.69276); B (-781.68249); C
(-781.68281); D (-781.69350). (d) B3LYP-IPCM/6–311+G**//
(m, br), 1561 (m), 1488 (m), 1467 (s), 1431 (s), 1339 (s), 1244 (s),
1202 (s), 1170 (s), 1004 (m), 939 (s), 923 (s), 880 (s), 825 (s), 764
(s). MS (EI, 70 eV) m/z = 235 (M+, 76.3), 219 (100), 203 (35.2),
191 (30.7), 177 (71.1), 163 (28.9), 155 (26.7), 147 (93.5), 137 (47.4),
120 (33.6), 109 (27.9). HRMS (EI, 70 eV): calcd. for C12H10FNO3
(M+) 235.06392, found 235.06341.
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B3LYP/6–311+G** total energies (au): A (-783.90064); B
(-783.90008); (-783.90043); (-783.90874). (e) MP2-
IPCM/6–311+G**//B3LYP/6–311+G** total energies (au): A
(-781.71039); B (-781.69618); C (-781.69634); D (-781.70942).
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11 P. Langer and T. Krummel, Chem.–Eur. J., 2001, 7, 1720.
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C
D
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1938 | Org. Biomol. Chem., 2009, 7, 1931–1938
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