A new approach to 3-hydroxyquinoline-2-carboxylic acid

Article abstract of DOI:10.1016/j.tet.2004.12.011

Quinoline-2-carboxylic acid derivatives cap the N-terminal of several natural cyclic peptides with antitumoral activity. A new and convenient route for the preparation of 3-hydroxyquinoline-2-carboxylic acid is discussed. The preparation of the title compound is accomplished by a four-step procedure from 3-hydroxyquinoline via MOM protection of the hydroxyl group, followed by a 1,2-addition of methyllithium to the quinoline ring with concomitant oxidation, and, finally, a two-step oxidation procedure for the transformation of the methyl group to the carboxylic acid along with removal of the MOM group. Furthermore, different attempts to its preparation led to other interesting quinolines, such as 2-chloro-3-hydroxyquinoline-4-carboxylic acid and a protected 3,3′-dihydroxy-2,2′-biquinoline.

Full text of DOI:10.1016/j.tet.2004.12.011

Tetrahedron 61 (2005) 1407–1411
A new approach to 3-hydroxyquinoline-2-carboxylic acid
Estela Riego,a, Nuria Bayo,a,b Carmen Cuevas,c Fernando Albericioa,b,
*
*
´
and Mercedes Alvarez
a,d,
´
*
aBarcelona Biomedical Research Institute, Barcelona Scientific Park, University of Barcelona, Josep Samitier 1-5, 08028 Barcelona, Spain
bDepartment of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
cPharmaMar, Avda de los Reyes 1, 28770 Colmenar Viejo, Madrid, Spain
dLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 29 October 2004; revised 3 December 2004; accepted 6 December 2004
Available online 22 December 2004
Abstract—Quinoline-2-carboxylic acid derivatives cap the N-terminal of several natural cyclic peptides with antitumoral activity. A new
and convenient route for the preparation of 3-hydroxyquinoline-2-carboxylic acid is discussed. The preparation of the title compound is
accomplished by a four-step procedure from 3-hydroxyquinoline via MOM protection of the hydroxyl group, followed by a 1,2-addition of
methyllithium to the quinoline ring with concomitant oxidation, and, finally, a two-step oxidation procedure for the transformation of the
methyl group to the carboxylic acid along with removal of the MOM group. Furthermore, different attempts to its preparation led to other
interesting quinolines, such as 2-chloro-3-hydroxyquinoline-4-carboxylic acid and a protected 3,30-dihydroxy-2,20-biquinoline.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Preliminary studies
3-Hydroxyquinoline-2-carboxylic acid 1 is a key element in
the synthesis of 2-fold symmetric bicyclic natural depsi-
peptides such as SW-163C, SW-163E,1 sandramycin,2 and
thiocoraline,3 and is incorporated into the peptide chain at
the N-terminal through an amide bond. The heterocyclic
chromophore plays a significant role in the DNA binding
properties of these compounds; hence it is crucial to their
biological activity.4
Due to the high value of metalation processes of quinolines
for the preparation of polyfunctionalized quinolines,6 it was
decided to study these reactions in commercially available
quinolines.
´
Based on the work of Queguiner et al. who described
directed lithiation of quinoline-2-carboxylic acid 2 with
lithium 2,2,6,6-tetramethylpiperidide (LTMP) at C-3,7 the
To the best of our knowledge, the only direct synthesis of
partially protected 3-hydroxyquinoline-2-carboxylic acid
derivatives has been described by Boger and Chen.5 These
authors used a modified Friedlander condensation of
2-aminobenzaldehyde with the O-methyloxime of ethyl
3-(benzyloxy)pyruvate to afford methyl 3-(benzyloxy)-
quinoline-2-carboxylate. The difficulty of the ring construc-
tion, as it was exemplified in the aforementioned
publication,5 prompted us to study the preparation of
3-hydroxyquinoline-2-carboxylic acid 1 from commercially
available quinoline derivatives through the introduction of
suitable functional groups onto the ring.
Scheme 1. Initial attempts at the preparation of 1. Reagents: (a) (i) LTMP,
THF, K78 8C, 1 h; (ii) B(OMe)3, K78 8C, 2 h; (iii) H2O2, NH4Cl aq, Et2O.
(b) (i) MOMCl, NaOH, Adogen, CH2Cl2; (ii) BuLi, THF, K78 8C, 2 h;
(iii) CO2, K78 8C/rt, 0.5 h; (iv) 2 N HCl (5: 75%). (c) POBr3, 105 8C,
4 h. (d) (i) LTMP, THF, K25 8C, 0.5 h; (ii) B(OR)3 (RZMe, iPr).
Keywords: Heterocycle; Biquinoline; ortho-Litiation; MOM; Cyclic
peptides.
* Corresponding authors. Fax: C34 93 403 71 26; e-mail
addresses: eriego@pcb.ub.es; albericio@pcb.ub.es; malvarez@pcb.ub.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.011

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E. Riego et al. / Tetrahedron 61 (2005) 1407–1411
introduction of an electrophile that could be transformed
into an alcohol function, such as a trialkylborate, in that
position was attempted. However, starting material was
recovered from several conditions tested (Scheme 1).8
The strategy was then changed and carbon dioxide was
chosen as electrophile with a lithiated hydroxyquinoline.
The first quinoline used was 2-chloro-3-hydroxyquinoline 4
(Scheme 1), readily prepared from 2-chloroquinoline 3,9 in
order to achieve a chloro-metal exchange. Methoxymethyl
ether (MOM) was used as protecting group of the
oxygenated function of 4 because it could be easily removed
under acidic conditions. After the hydroxyl protection of
4, the chloroquinoline was treated with n-butyllithium at
K78 8C for 2 h followed by bubbling in carbon dioxide.
However, the reaction product was 2-chloro-3-hydroxy-
quinoline-4-carboxylic acid 5 (Scheme 1), which was
obtained in good yield (75% from 4) and originated from
the direct metalation at C-4 and deprotection of the hydroxyl
group during work up. It is remarkable that compound 5 was
isolated as the sole product in this process despite the use
of BuLi as base, which can be added to quinolines, as later
described in this paper.
Scheme 2. Directed lithiation of 3-(methoxymethoxy)quinoline 8.
dimethylaminoethoxide (BuLi-LiDMAE), which induces
a regioselective C-a lithiation of pyridine derivatives.14
The results obtained are summarized in Table 1. At low
temperature, neither LDA (entry 1) or BuLi-LiDMAE
(entry 2) or t-BuLi (entry 3) worked in the ortho-lithiation
process because starting material was recovered in the first
case, and the corresponding 2-alkyl-3-(methoxymethoxy)-
quinolines15,16 were isolated when an alkyllithium was used
as base.
Table 1. Directed lithiation of 3-(methoxymethoxy)quinoline 8
Compound 5 could be useful as precursor to non-peptide
antagonists for the human neurokinin-3 receptor, such as
(S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-
carboxamide.10
Entry
Conditions
Ratio 1:9:8a
1
2
3
4
5
6
7
8
9
LDA (3 equiv), K78 8C, 2 h
BuLi-LiDMAE (3 equiv), K78 8C, 2 hb
t-BuLi (3 equiv), K78 8C, 2 h
LTMP (2 equiv), K78 8C, 2 h
LTMP (3 equiv), K78 8C, 2 h
LTMP (3 equiv), K78 8C, 5 h
LTMP (2 equiv), K40 8C, 1 h
LTMP (2 equiv), 25 8C, 6 h
LDA (2 equiv), 25 8C, 6 h
0:0:1
c
—
—
d
1.4:1:4.3
1.3:1:3.1
The next route explored involved the preparation of
2-bromo-3-hydroxyquinoline 6 (Scheme 1), which could
undergo bromo-metal exchange more easily. Thus, 3 was
treated with phosphorous oxybromide, affording 2-bromo-
quinoline which was transformed into hydroxyquinoline 6
by ortho-lithiation by LTMP, following the procedure
described for 4.9 However, the halogen–metal interchange
and carboxylation failed, resulting in a complex mixture.
This could be due to the competition of directed metalation
at C-4, reduction of the C–Br bond, and addition of BuLi to
the quinoline ring.11
e
—
0:1:5
0:15:1
0:14:1
a Ratio determined by 400 MHz 1H NMR analysis of the crude reaction.
b The solvent used was a mixture of hexane/THF 2:1.
c The reaction product was 2-butyl-3-(methoxymethoxy)quinoline pro-
duced by 1,2-addition of butyllithium to the quinoline ring with
concomitant oxidation.
d The reaction product was 2-tert-butyl-3-(methoxymethoxy)quinoline
coming from the 1,2-addition of t-butyllithium to the quinoline ring
with concomitant oxidation.
e A complex reaction mixture was isolated, but starting material was
detected by 400 MHz 1H NMR analysis.
To avoid competing reactions produced in the halogen–
metal exchange from 4 and 6, ortho-metalation in a
protected 3-hydroxyquinoline which, to the best of our
knowledge, has not been used in ortho-directing processes,
was then studied.
When LTMP was used at K78 8C (entry 4), the target
compound was obtained in low yield (21%). The starting
material as well as 2,20-biquinoline 9 were also recovered.
Formation of 9 could be explained by addition of the 2-lithio
derivative to 8 and subsequent air oxidation.17 This result
was not substantially improved using more equivalents of
base (entry 5, 24% yield) or longer reaction time (entry 6).
At higher temperatures, the ratio of 9 increased (entries 7–8)
and no formation of 1 was observed.
2.2. ortho-Metalation studies in 3-hydroxyquinoline 7
3-Hydroxyquinoline 7 was prepared from commercially
available 3-aminoquinoline by the Bucherer reaction.12
Although only a few examples of metalation of methoxy-
methoxy derivatives have been reported in the literature,13
the MOM group was chosen as hydroxyl protecting owing
to its facile introduction and elimination.
Other electrophiles, such as D2O, MeI, ClCO2Me, and
DMF, were tested under the best carboxylation conditions
(entry 5). The major reaction product was the starting
material and 2,20-biquinoline 9 was also isolated in similar
ratios as before.
Thus, lithiation of 3-(methoxymethoxy)quinoline 8 was
examined under different conditions by trapping the anion
with carbon dioxide (Scheme 2).
The low yield in the preparation of 1 by ortho-lithiation of
3-(methoxymethoxy)quinoline 8 could be due to the low
reactivity of this quinoline versus lithium dialkylamides as
The bases used were the well-known lithium diisopropyl-
amide (LDA) and LTMP, as well as t-BuLi and the
basic reagent composed of n-butyllithium and lithium

E. Riego et al. / Tetrahedron 61 (2005) 1407–1411
1409
well as the fast formation of the 2,20-biquinoline 9 previous
to the total metalation of the starting material, even at low
temperature.
electron-donating substituent.20 Moreover, the overall yield
of 1 was 62% after three steps from the readily available
3-(methoxymethoxy)quinoline, and no purifications were
required. The final product was isolated simply by filtration,
a key advantage of this method when considering the poor
solubility of the target compound in organic solvents.
Another important conclusion of all of these experiments
relates to the selectivity of the lithiation. The formation of
2,20-biquinoline and 3-hydroxyquinoline-2-carboxylic acid
demonstrates that lithiation occurred exclusively at C-2. In
the literature, metalation of 3-(methoxymethoxy)pyridine
was reported at C-4.13c,d
3. Conclusion
In conclusion, we have described an alternative synthesis of
3-hydroxyquinoline-2-carboxylic acid from the commer-
cially available 3-aminoquinoline with a better yield than
that reported for the existing synthesis. This new route does
not require any purification step and the target compound
precipitates from the reaction mixture, simplifying its
handling and isolation. These advantages should facilitate
the preparation of compounds bearing the biologically
important moiety. In addition, other functionalized quino-
lines, such as 2-chloro-3-hydroxyquinoline-4-carboxylic
acid and a protected 3,30-dihydroxy-2,20-biquinoline, were
prepared by ortho-metalation processes.
Despite the formation of 9 and the presence of the starting
material, 3-hydroxyquinoline-2-carboxylic acid 1 was
isolated with high purity (93% by HPLC analysis) after a
simple acid–base work up.
Otherwise, 3,30-bis-(methoxymethoxy)-2,20-biquinoline 9
was prepared in 70% yield when metalation of 8 was
carried out with LTMP at room temperature for 6 h.
Furthermore, 9 was also prepared with LDA under the
same conditions in a similar rate (entry 9). This compound
could be interesting as a ligand in metal complexes,18 or in
dye laser applications.19
2.3. Preparation of 3-hydroxy-2-quinolinecarboxylic
acid 1
4. Experimental
4.1. General
Since 1,2-addition to 3-(methoxymethoxy)quinoline 8 is an
important side-reaction in the ortho-lithiation process, and
taking into account that methyl aromatic compounds can be
oxidized to the corresponding carboxylic acid, we decided
to take advantage of that reactivity and follow a strategy
starting from 8 and based on nucleophilic addition followed
by oxidation to render the acid 1. Thus, the introduction of
methyl group was accomplished by addition of methyl-
lithium to 3-(methoxymethoxy)quinoline 8 (Scheme 3),
which produced a mixture of the corresponding inter-
mediate 1,2-dihydroquinoline and 2-methylquinoline 10
(from the partial air oxidation of the dihydroquinoline).
Subsequent treatment of the reaction mixture with
ammonium cerium (IV) nitrate (CAN) led to 10 in high
yield with total regioselectivity.
All reagents were commercial products (Fluka, Aldrich
or Acros) and used as received. THF was freshly distilled
from sodium/benzophenone. Dichloromethane (99.99%
anhydrous) and 1,4-dioxane (99.98% anhydrous) were
purchased from SDS and used as received. Reactions
involving air and/or moisture sensitive reagents were
conducted under an atmosphere of argon. Melting points
were recorded in a Bu¨chi apparatus and are uncorrected.
IR spectra were obtained using a Thermo Nicolet Nexus
spectrophotometer. NMR spectra were acquired with Varian
Gemini-300 (300 MHz) and Mercury-400 (400 MHz)
spectrometers; data are given on the d scale referenced to
TMS. Mass spectra were measured in the electron impact
(EI) mode with a Hewlett-Packard model 5989A spectro-
meter. High-resolution mass spectra were performed on an
´
AutoSpec/VG by Unidad de Espectrometrıa de Masas de
Santiago de Compostela (Spain). HPLC was carried
out using a Waters 996 Photodiode Array Detector, a
SYMMETRY C18 column (4.6!150 mm, 5 mm) with H2O
(0.045% TFA) and acetonitrile (0.036% TFA) as eluents.
Analytical TLC was performed on SiO2 (silica Gel 60 F254,
Merck) and spots were visualized with UV light. Column
chromatography was carried out on SiO2 (silica Gel 60 SDS
0.035–0.070 mm).
Scheme 3. Preparation of 3-hydroxyquinoline-2-carboxylic acid 1.
Reagents: (a) (i) MeLi, THF, 0 8C, 1 h; (ii) CAN, acetone, 30 min.
(b) (i) SeO2, 1,4-dioxane, reflux, 1.5 h; (ii) H2O2, HCO2H, 0 8C, overnight.
To carry out the oxidation of the methyl group in 10, a
strong oxidant, such as KMnO4, was tested due to the low
reactivity of methylquinolines. Using these drastic con-
ditions, a complex crude reaction was obtained, presumably
since ring cleavage could also occur. This problem was
overcome using a two-step procedure of oxidation of 10
to the corresponding aldehyde with selenium dioxide,
followed by oxidation by hydrogen peroxide in formic
acid. In these acidic conditions the MOM group was
removed, and 3-hydroxy-2-quinolinecarboxylic acid 1 was
isolated in 70% yield. It is noteworthy that the last oxidation
step proceeded with high yield, despite the presence of an
4.1.1. 2-Chloro-3-hydroxyquinoline-4-carboxylic acid
(5). To a suspension of 2-chloro-3-hydroxyquinoline 4
(100 mg, 0.56 mmol) in dichloromethane (4 mL) was added
2 N NaOH (1 mL), and Adogen (55 mg) at room tempera-
ture. After 30 min, MOMCl was added and the mixture was
stirred for 45 min. Water (5 mL) was added, and the product
was extracted with dichloromethane (3!5 mL). After
concentration of organic layers, the residue was chromato-
graphed on silica gel (5/1 hexane/ethyl acetate) to
provide pure protected hydroxyquinoline in 86% yield.

1410
E. Riego et al. / Tetrahedron 61 (2005) 1407–1411
n-Butyllithium (0.16 mL of 1.6 M solution in hexane,
0.25 mmol) was then added dropwise to a K78 8C stirred
solution of protected quinoline (46.3 mg, 0.21 mmol) in dry
THF (1 mL). The solution was stirred for 2 h at the same
temperature. Carbon dioxide was bubbled for 2 min, and the
reaction mixture was allowed to warm to room temperature.
Stirring was continued for 0.5 h and 2 N HCl (1 mL) was
then added. After usual work up, 2-chloro-3-hydroxyquino-
line-4-carboxylic acid 5 was isolated in 87% yield: 1H NMR
(DMSO-d6, 400 MHz) d 8.47 (1H, d, JZ8.3 Hz), 7.86 (1H,
d, JZ7.8 Hz), 7.62–7.55 (2H, m); 13C NMR (DMSO-d6,
100 MHz) d 168.7 (C), 147.8 (C), 143.7 (C), 140.7 (C),
128.3 (CH), 128.2 (CH), 127.0 (CH), 125.0 (C), 124.3 (CH),
119.5 (C); MS, m/z 225 (MCC2, 19), 223 (MC, 54), 207
(44), 205 (100), 179 (23), 177 (56), 151 (12), 149 (36), 114
(60); HRMS calcd for C10H6ClNO3: 223.0036, found:
223.0040.
for 1 h, the mixture was treated with a saturated aqueous
solution of NH4Cl (5 mL) and extracted with dichloro-
methane (3!15 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was dissolved in acetone (2 mL) and treated with an
aqueous solution of ammonium cerium (IV) nitrate (3.89 g
in 10 mL) for 30 min. The mixture was extracted with
dichloromethane (3!15 mL) and dried over Na2SO4, and
the filtrate was concentrated under reduced pressure to give
0.63 g (88%) of an orange syrup, which was used without
1
further purification: H NMR (CDCl3, 400 MHz) d 7.98
(1H, dd, JZ8.2, 0.9 Hz), 7.68 (1H, dd, JZ8.2, 1.2 Hz), 7.61
(1H, s), 7.54 (1H, ddd, JZ8.2, 7.0, 1.2 Hz), 7.43 (1H, ddd,
JZ8.2, 7.0, 0.9 Hz), 5.33 (2H, s), 3.52 (3H, s), 2.68 (3H, s);
13C NMR (CDCl3, 75 MHz) d 152.3 (C), 149.8 (C), 134.8
(C), 131.5 (CH), 129.6 (CH), 128.2 (CH), 127.6 (CH), 123.8
(C), 121.7 (CH), 95.7 (CH2), 57.2 (CH3), 16.7 (CH3);
HRMS calcd for C12H13NO2: 203.0946, found: 203.0943.
4.1.2. 3-(Methoxymethoxy)quinoline (8). Methoxymethyl
chloride (0.80 mL, 10.6 mmol) was slowly added to a
solution of 3-hydroxyquinoline 7 (1.02 g, 7.1 mmol) and
diisopropyl ethylamine (1.4 mL, 8.5 mmol) in dry dichloro-
methane (4 mL) at 0 8C. The solution was warmed to room
temperature overnight, and then water (5 mL) was added.
The product was extracted with dichloromethane (3!
10 mL), washed with 2 M sodium hydroxide (10 mL), and
water (10 mL), and dried over Na2SO4. Removal of the
solvent gave 0.86 g (67%) of a red oil, which was used
without further purification: 1H NMR (CDCl3, 400 MHz) d
8.72 (1H, d, JZ2.8 Hz), 8.05 (1H, dd, JZ8.1, 1.5 Hz), 7.73
(1H, dd, JZ8.2, 1.1 Hz), 7.68 (1H, d, JZ2.8 Hz), 7.57 (1H,
ddd, JZ8.2, 7.0, 1.5 Hz), 7.50 (1H, ddd, JZ8.1, 7.0,
1.1 Hz), 5.31 (2H, s), 3.53 (3H, s); 13C NMR (CDCl3,
75 MHz) d 150.4 (C), 144.5 (CH), 144.0 (C), 129.0 (CH),
128.6 (C), 127.0 (CH), 126.9 (CH), 126.8 (CH), 116.5 (CH),
94.6 (CH2), 56.2 (CH3); MS, m/z 189 (MC, 67), 159 (19),
128 (18), 116 (31), 101 (13), 89 (19), 63 (13), 45 (100);
HRMS calcd for C11H11NO2: 189.0790, found: 189.0793.
4.1.5. 3-Hydroxyquinoline-2-carboxylic acid (1). Sele-
nium dioxide (0.36 g, 3.3 mmol) was added to a solution of
10 (0.63 g, 3.1 mmol) in dry 1,4-dioxane (30 mL). The
reaction mixture was refluxed for 1 h and then cooled to
room temperature and filtered through a pad of Celite. The
filtrate was evaporated to give a residue which was
dissolved in formic acid (1 mL) and cooled to 0 8C.
Hydrogen peroxide (1.7 mL of 30% solution in water,
15.5 mmol) was slowly added and the mixture was allowed
to stand overnight between 0 and 10 8C. A precipitate
formed and was collected by filtration, washed with cold
water, and dried to give 3-hydroxyquinaldic acid as a yellow
1
solid (0.41 g, 70%): mp 187–190 8C (decomp.); H NMR
(CDCl3, 400 MHz) d 8.22 (1H, dd, JZ8.6, 1.2 Hz), 8.01
(1H, s), 7.83 (1H, dd, JZ8.4, 1.6 Hz), 7.70 (1H, ddd, JZ
8.6, 7.0, 1.6 Hz), 7.64 (1H, ddd, JZ8.4, 7.0, 1.2 Hz), 3.27
(1H, br s); 13C NMR (DMSO-d6, 100 MHz) d 166.7 (C),
152.2 (C), 138.1 (C), 137.9 (C), 130.7 (C), 128.8 (CH),
128.4 (CH), 126.6 (CH), 126.2 (CH), 122.3 (CH); IR (KBr)
3449, 1681; MS, m/z 189 (MC, 91), 171 (39), 145 (70), 143
(100), 117 (63), 115 (91), 89 (52); HRMS calcd for
C10H7NO3: 189.0426, found: 189.0428.
4.1.3. 3,30-Bis-methoxymethoxy-2,20-biquinoline (9).
n-Butyllithium (0.27 mL of 1.6 M solution in hexane,
0.43 mmol) was added at 0 8C to a stirred solution of
2,2,6,6-tetramethylpiperidine (73 mL, 0.44 mmol) in dry
THF (1.2 mL). After 10 min, a solution of 8 (55.2 mg,
0.29 mmol) in dry THF (0.5 mL) was added dropwise, and
the reaction was stirred at room temperature for 6 h.
Saturated aqueous solution of NH4Cl (5 mL) was added
and the aqueous layer was extracted with dichloromethane
(3!10 mL). Removal of the solvent followed by purifi-
cation by flash chromatography (3/1 hexane/ethyl acetate)
provided pure compound 9: 1H NMR (CDCl3, 400 MHz) d
8.16 (2H, dd, JZ7.9, 1.5 Hz), 7.89 (2H, s), 7.81 (2H, dd,
JZ8.0, 1.3 Hz), 7.60 (2H, ddd, JZ8.2, 8.0, 1.5 Hz), 7.54
(2H, ddd, JZ8.2, 7.9, 1.3 Hz), 5.21 (4H, s), 3.40 (6H, s); 13C
NMR (CDCl3, 100 MHz) d 151.0 (C), 149.6 (C), 143.8 (C),
129.6 (CH), 129.1 (C), 127.3 (CH), 127.1 (CH), 126.7 (CH),
117.2 (CH), 95.0 (CH2), 56.1 (CH3); MS, m/z 376 (MC, 16),
331 (100), 301 (25), 285 (40).
Acknowledgements
This work was partially supported by CICYT (BQU2003-
0089) and Barcelona Scientific Park. The authors are
grateful to Greg Qushair (University of Barcelona), Drs.
´
´
´
Andres Francesch and Juan Jose Gonzalez (PharmaMar)
for previous work carried out towards the preparation of
3-hydroxyquinoline-2-carboxylic acid. E. R. thanks to
Principado de Asturias for a postdoctoral fellowship.
References and notes
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at 0 8C was added methyllithium (2.8 mL of 1.5 M solution
in diethyl ether, 4.2 mmol) dropwise. After stirring at 0 8C
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´
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15. 2-Butyl-3-(methoxymethoxy)quinoline. 1H NMR (CDCl3,
400 MHz): d 8.00 (1H, d, JZ8.2, 1.6 Hz), 7.69 (1H, dd, JZ
8.1, 1.2 Hz), 7.63 (1H, s), 7.54 (1H, ddd, JZ8.1, 7.1, 1.6 Hz),
7.44 (1H, ddd, JZ8.2, 7.1, 1.2 Hz), 5.34 (2H, s), 3.53 (3H, s),
3.03 (2H, t, JZ7.9 Hz), 1.81–1.76 (2H, m), 1.49–1.43 (2H, m),
0.97 (3H, t, JZ7.5 Hz); 13C NMR (CDCl3, 100 MHz): d 156.6
(C), 149.2 (C), 143.2 (C), 128.3 (CH), 128.1 (C), 126.9 (CH),
126.5 (CH), 126.0 (CH), 115.2 (CH), 94.3 (CH2), 56.1 (CH3),
33.7 (CH2), 30.8 (CH2), 22.8 (CH2), 14.0 (CH3).
´
6. For a review, see: Mongin, F.; Queguiner, G. Tetrahedron
2001, 57, 4059–4090.
7. Rebstock, A.-S.; Mongin, F.; Trecourt, F.; Queguiner, G.
Tetrahedron Lett. 2002, 43, 767–769.
´
´
8. Trimethyl borate and triisopropyl borate were used as
electrophiles under different reaction conditions: temperatures
from K25 8C to room temperature, and reaction times between
1 and 24 h.
1
16. 2-tert-Butyl-3-(methoxymethoxy)quinoline. H NMR (CDCl3,
´
9. Marsais, F.; Godard, A.; Queguiner, G. J. Heterocycl. Chem.
1989, 25, 1589–1594.
400 MHz): d 8.01 (1H, d, JZ8.3 Hz), 7.68 (1H, dd, JZ8.4,
1.2 Hz), 7.66 (1H, s), 7.53 (1H, ddd, JZ8.4, 7.1, 1.6 Hz), 7.43
(1H, ddd, JZ8.3, 7.1, 1.2 Hz), 5.36 (2H, s), 3.54 (3H, s), 1.54
(9H, s); 13C NMR (CDCl3, 100 MHz): d 160.5 (C), 150.1 (C),
145.5 (C), 129.1 (CH), 128.0 (C), 126.6 (CH), 126.1 (2(CH),
115.6 (CH), 94.0 (CH2), 56.2 (CH3), 38.9 (C), 28.7 (CH3).
17. The addition adduct 1,2-dihydro-2,20-biquinoline was detected
by 400 MHz 1H NMR in some reaction mixtures.
10. Giardina, G. A. M.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.;
Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt, D. B.;
Rigolio, R.; Luttmann, M.; Cavagnera, S.; Foley, J. J.;
Vecchietti, V.; Hay, D. W. P. J. Med. Chem. 1999, 42,
1053–1065.
11. (a) Gilbchirst, T. L. In Heterocyclic Chemistry; Gilbchirst,
T. L., Ed. 2nd ed.; Longman Scientific and Technical: Essex,
1992; p 161. (b) Wolf, C.; Lerebous, R. J. Org. Chem. 2003,
68, 7077–7084. (c) Amiot, F.; Cointeaux, L.; Silve, E. J.;
Alexakis, A. Tetrahedron 2004, 60, 8221–8231.
12. Bergeron, R. J.; Wiegand, J.; Weimar, W. R.; Vinson, J. R. T.;
Bussenius, J.; Yao, G. W.; McManis, J. S. J. Med. Chem. 1999,
42, 95–108.
18. Some examples: (a) Li, X.; Illigen, J.; Nieger, M.; Michel, S.;
Schalley, C. A. Chem. Eur. J. 2003, 9, 1332–1347. (b) Moya,
´
´
S. A.; Guerrero, J.; Pastene, R.; Azocar-Guzman, I.; Pardey,
A. J. Polyhedron 2002, 21, 439–444. (c) Charette, A. B.;
Marcoux, J.-F.; Molinaro, C.; Beauchemin, A.; Brochu, C.;
Isabel, E. J. Am. Chem. Soc. 2000, 122, 4508–4509.
19. Naumann, C.; Langhals, H. Synthesis 1990, 279–281.
20. Dodd, R. H.; Le Hyaric, M. Synthesis 1993, 295–297.
13. (a) Snieckus, V. Chem. Rev. 1990, 90, 879–933. (b) Shimano,