The deprotonative metalation of [1,2,3]triazolo[1,5-a]quinoline. Synthesis of 8-haloquinolin-2-carboxaldehydes

Article abstract of DOI:10.1016/j.tet.2009.03.058

New highly functionalized triazoloquinolines were synthesized by applying polar organometallic methods. Double metalation and functionalization provided 3,9-dihalogenated triazoloquinolines. Ring opening of the triazole with loss of nitrogen has been perf

Full text of DOI:10.1016/j.tet.2009.03.058

Tetrahedron 65 (2009) 4410–4417
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The deprotonative metalation of [1,2,3]triazolo[1,5-a]quinoline.
Synthesis of 8-haloquinolin-2-carboxaldehydes
a
a
,
b,
*
*
´ ´
Rafael Ballesteros-Garrido , Frederic R. Leroux , Rafael Ballesteros
,
b,
a,
*
*
´
Belen Abarca , Françoise Colobert
a
´ ´
´
Laboratoire de stereochimie, CNRS, Universite de Strasbourg (ECPM), 25 Rue Becquerel, 67087 Strasbourg, France
b
´
´
´
Departamento de Qu´ımica Organica, Facultad de Farmacia, Universidad de Valencia, Avda. Vicente Andres Estelles s/n, 46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
New highly functionalized triazoloquinolines were synthesized by applying polar organometallic
methods. Double metalation and functionalization provided 3,9-dihalogenated triazoloquinolines. Ring
opening of the triazole with loss of nitrogen has been performed for the first time with 3,9-dihalogenated
triazoloquinolines allowing the access toward 8-haloquinolin-2-carboxaldehydes under oxidant-free
conditions. This approach demonstrates that the triazole ring can be used as protecting group of 2-
quinolinecarboxaldehydes, activating the C9-position for lithiation and functionalization by triazole ring
opening. 8-Haloquinoline-2-carbaldehydes become in this way readily available.
Received 10 December 2008
Received in revised form 17 March 2009
Accepted 18 March 2009
Available online 27 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
remote-lithiation at the 4-position allowed the preparation of tri-
azoloquinoline 4. The opening of the triazole ring in the presence of
Numerous quinoline derivates, containing planar
p
-electron de-
acetic acid gave rise to dihydrofuro[3,4-b]quinoline 5, formally
a 2,3-disubstituted quinoline.20 This methodology affords exclu-
sively C3- and C4-disubstituted triazoloquinolines (i.e., 4).
Comparing the reactivity of [1,2,3]triazolo[1,5-a]quinoline (1)
and [1,2,3]triazolo[1,5-a]pyridine toward organometallic bases like
LDA or BuLi, as reported by Jones and us,23,24 a striking difference in
regioselectivity can be observed. Whereas [1,2,3]triazolo[1,5-
a]pyridine is selectively deprotonated at the 7-position, the
ficientpolycyclicringsystemscanbefound innaturalproducts1–3 and
belong to the privileged structures in pharmaceutical research.4–9 In
addition, the quinoline substructure hasbeenefficiently incorporated
in the synthesis of heterodentate P,N-ligands,10–12 like QUINAP,13,14
with application in asymmetric catalysis.
Many efforts were devoted to the synthesis of this heterocyclic
moiety and its functionalization. The most classical methods like
the Skraup15 or Doebner–Miller synthesis16 require drastic condi-
tions or have low yields.
Due to our ongoing interest in the chemistry of [1,2,3]tri-
azolo[1,5-a]pyridine-based heterocycles,17–19 we focused our at-
tention on [1,2,3]triazolo[1,5-a]quinolines, whose parent structure
1 is depicted in Scheme 1.
ii, iii
H
i
N
CH3
N
N
N
N
O
1 (92%)
Although readily accessible, [1,2,3]triazolo[1,5-a]quinolines
have been rarely investigated during the last 20 years.20–22 Their
functionalization afforded compounds with different functional
groups on the nitrogenated ring. Strong bases like lithium di-iso-
propylamide (LDA) undergo the deprotonative metalation20 only at
the 3-position affording compounds 2 after trapping with electro-
philes (Scheme 1).20,22 In previous works Jones and us applied this
protocol to obtain the carboxamide 3, which after subsequent
vi, vii
iv, v
CONEt2
El
N
N
3 (80%)
N
N
El = COOH
N
N
2 (78-84%)
Ar
Ar
OH
ix
iv,viii
O
N
CONEt2
N
N
N
4 (40-60%)
5 Ar = p-CH3OC6H4
* Corresponding authors. Tel.: þ33390242640; fax: þ33390242742.
E-mail addresses: frederic.leroux@unistra.fr (F.R. Leroux), rafael.ballesteros@
uv.es (R. Ballesteros), belen.abarca@uv.es (B. Abarca), francoise.colobert@unistra.fr
(F. Colobert).
Scheme 1. Reagents and conditions: (i) SeO2, dioxane. (ii) H2NNH2, MeOH. (iii) MnO2,
CHCl3. (iv) LDA, THF ꢀ40 ꢁC. (v) El-X. (vi) SOCl2. (vii) HNEt2. (viii) ArCHO. (ix) AcOH,
heat.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.058

R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
4411
Previous work
LDA
with iodomethane a mixture of C3 and C9 mono- and disubstituted
derivatives in
(Scheme 2, Table 1, entry 4).
6
9
5
5
a
ratio 2a/6/7a¼37:32:31 and 88% conversion
4
7
8
6
7
4
3
N
1N
N
1N
3
N
N
BuLi, LDA
2
2
This work
i,ii
+
[1,2,3]triazolo[1,5-a]pyridines
[1,2,3]triazolo[1,5-a]quinolines
N
CH3
N
N
N
N
N
CH3
N
N
N
Figure 1. Metalation sites in [1,2,3]triazolo[1,5-a]quinolines (1) versus [1,2,3]tri-
azolo[1,5-a]pyridines.
1
2a
6
i = BuLi (1.2 eq), THF,
-78 °C, 1h
+
CH3
N
N
9-position in [1,2,3]triazolo[1,5-a]quinoline seems to be much less
ii = H3CI
CH3
N
reactive, favoring deprotonative metalation at the 3-position,
a to
7a
the ring nitrogen (Fig. 1). In contrast, this kind of C3-metalation is
not observed in triazolopyridines under similar conditions. Very
Scheme 2.
´
recently, Mongin, Queguiner, and Abarca reported on the metal-
Under these conditions, the metalation was no longer
regioselective at C3 as in the case of the LDA-promoted depro-
tonative metalation of triazoloquinoline 1. A mixture of three
metalation products was obtained, indicating that the metal-
ation in position 9 is possible and that also a double metalation
can be achieved.
We studied also the metalation of [1,2,3]triazolo[1,5-a]quinoline
(1) with LiTMP in THF at ꢀ78 ꢁC during 2 h, which resulted in
a selective metalation of the 3-position.
Trapping of the organolithium intermediate with iodomethane
afforded compound 2a in a yield of 86%. After deuteration with
CD3OD, triazoloquinoline 2b was obtained in 96% yield. Chloro-
trimethylsilane gave the corresponding silylated derivative 2c in
quantitative yield, iodine compound 2d in a yield of 72% and
(1R,2S,5R)-(ꢀ)-menthyl-(S)-p-toluenesulfinate the sulfoxide 2e in
82% yield (Scheme 3). In case of trapping with iodomethane, CD3OD
and iodine, trace amounts of disubstituted derivatives were
detected in the 1H NMR. Figure 2 shows the 1H NMR spectra of
[1,2,3]triazolo[1,5-a]quinoline (1) and the corresponding deuter-
ated analogue 2b.
ation of [1,2,3]triazolo[1,5-a]pyridine using magnesium- and cad-
mium ate complexes.25
In the present work, we studied the deprotonative metalation of
the 9-position (peri position) of [1,2,3]triazolo[1,5-a]quinoline (1),
as this will open route to 8-substituted quinolines.
The functionalization of quinolines at the 8-position by metal-
ation and/or bromine/lithium exchange has been reported.26–38
However, lack of regioselectivity is often a major drawback. Re-
cently, Knochel et al. reported on the functionalization of quino-
lines via magnesiation reactions allowing after successive
protection at C4 and C3, a metalation at the C8 position.39 We de-
cided to study the deprotonative metalation of triazoloquinolines 1
under different metalation conditions, changing the base, time,
temperature, and solvent.
2. Results and discussion
We observed that the metalation of [1,2,3]triazolo[1,5-a]quino-
line (1) with butyllithium in THF at ꢀ78 ꢁC afforded after trapping
Table 1
Metalation of [1,2,3]triazolo[1,5-a]quinoline (1) applying different bases and metalation conditions
+
i) Base, solvent,
N
N
time, temperature
CH3
N
N
ii) H3CI
CH3
6
N
N
2a
N
N
N
+
1
CH3
N
N
CH3
N
7a
Entry
Basea
Solvent
t (h)
T (ꢁC)
ꢀ78 ꢁ
2ab
6b
7ab
Conv.b
1
2
3
4
5
6
7
8
LiTMP
LDA
t-BuLi
BuLid
BuLi/KO t-Bu
BuLi/PMDTA
BuLi
BuLi
BuLi
BuLi
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Tol
2 h
4 h
2 h
1 h
2 h
2 h
2 min
1 h
2 h
2 h
2 h
2 h
C
91c
10020
88
0
9
100%
84%
100%
88%
59%
64%
82%
75%
71%
83%
33%
100%
ꢀ40 ꢁC
ꢀ78 ꢁ
ꢀ78 ꢁ
C
C
0
32
0
12
31
0
0
9
8
5
0
37
ꢀ78 ꢁC
ꢀ78 ꢁC
ꢀ78 ꢁC
ꢀ78 ꢁC
ꢀ78 ꢁC
100
100
41
50
54
100
90
0
0
50
42
41
0
3
0
9
10
11
12
0
ꢁC
BuLi
0 ꢁ
C
C
7
BuLie
THF
ꢀ78 ꢁ
82c
a
Base: 1.0 equiv.
b
c
Ratios determined from the integration values of the 1H NMR spectra of the crude reaction mixtures.
Isolated yield.
BuLi: 1.2 equiv.
Base (3.0 equiv) was employed.
d
e

4412
R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
So far, no base system allowed a regioselective metalation at the
9-position in order to determine if and in which way the 9-Li in-
termediate is converted into the 3-Li intermediate.
i) LiTMP (1.0 eq)
THF, -78 °C 2h
N
Li
N
N
When an excess of base was used (3.0 equiv of BuLi) the dime-
thylated product 7a was obtained in 82% yield after trapping with
iodomethane. Although no regioselective metalation at C9 could be
achieved, the double metalation undergoes in excellent yield.
In order to achieve a selective metalation at C9, the C3-position
had to be protected toward metalation by means of a trimethylsilyl
group. The protected triazoloquinoline 2c could then be success-
fully deprotonated at C9, although an excess of butyllithium
(1.7 equiv) had to be used in order to achieve complete conversion.
9-Methyl-3-(trimethylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (9) was
obtained in excellent yield after trapping with iodomethane.
Deprotection with tetrabutyl ammonium fluoride in THF at room
temperature afforded the triazoloquinoline 6 (Scheme 4).40 This
compound was obtained in an excellent overall yield of 77% starting
from quinaldine, revealing the general utility of the triazole sub-
structure. However, when the organolithium intermediate was
trapped with iodine, the iodo-derivative 8 could not be isolated in
pure form, neither by crystallization nor by column chromatogra-
phy, as this compound readily decomposed on silica gel.
N
N
N
1
ii) El-X
2a El = CH3 (86%)
2b El = D (96%)
2c El = Si(CH3)3 (99%)
2d El = I (72%)
El
N
2e El = (S)-S(O)-p-Tol (82%)
N
N
2a-e
Scheme 3.
Next, the effect of different reaction conditions (base and tem-
perature) and solvent (THF and toluene) on the outcome of the
reaction was studied (Table 1) in order to perform a selective
metalation at C9.
The metalation with LiTMP and tert-butyllithium afforded
mainly metalation at the sterically more accessible 3-position
(entries 1–3) albeit with trace amounts of dimetalation products.
When the Schlosser superbase (butyllithium/potassium tert-but-
oxide) was employed (entry 5), still the 3-position was exclusively
metalated, however, with a decreased conversion. Almost the same
result was obtained using butyllithium in presence of PMDTA
(N,N,N0,N00,N00-pentamethyl diethylene triamine, entry 6). Thus,
amide bases and t-BuLi lead to an exclusive metalation at the 3-
position, without any formation of 9-metalation product. The
metalation at the 9-position cannot be performed with tert-butyl-
lithium, probably for steric reasons. However, as the 3-Li in-
termediate formed under these conditions does not equilibrate
with the 9-Li intermediate, we can conclude that the metalation
using alkyl bases occurs under non-reversible conditions at C3.
When a slight excess of butyllithium was employed, a mixture of
3- and 9-metalation products together with a 3,9-dimetalation
product was obtained in a ratio of 37:32:31 (entry 4), indicating
that 9-metalation is possible.
i) BuLi (1.7 eq),
THF, -78 °C, 2h
ii) H3CI
Si(CH3)3
N
Si(CH3)3
N
N
2c
N
CH3
N
N
9 (98%)
i) BuLi 1.7 eq.
THF -78 °C, 2h
ii) I2
TBAF, THF
25 °C, 1h
N
N
Si(CH3)3
N
N
CH3
I
N
N
8
6 (87%)
Scheme 4.
By comparing different metalation times using butyllithium as
base (now under stoichiometric conditions), a slightly higher re-
activity of the 9-position could be deduced (entry 7, Table 1). The
amount of dilithiated intermediate, as well as the ratio between 3-
and 9-metalation remained more or less unchanged (entries 7 to 9)
at ꢀ78 ꢁC and only increased degradation was observed up to 12 h.
At higher temperature (entry 10) only the metalation product at
position 3 was observed.
As shown in Table 1 (entry 12) a double metalation of the tri-
azoloquinoline 1 could be achieved with an excess of butyllithium
affording compounds 7a–d after trapping with iodomethane, io-
dine, 1,2-dibromo-tetrafluoroethane, and 1,1,2-trichloro-1,2,2-tri-
fluoroethane, respectively (Scheme 5).
i) BuLi (3.0 eq)
THF, -78 °C, 2h
ii) El-X
N
El
N
N
N
N
El
N
1
7a El = CH3 (82%)
7b El = I (79%)
7c El = Br (74 %)
7d El = Cl (71%)
El-X= H3CI, I2 CF Br-CF Br,
,
2
2
CFCl2-CF2Cl
Scheme 5.
Due to the increasing interest on fluorinated compounds on one
side and the importance of polynitrogenated heterocycles (pyr-
azoles, triazoles, .) on the other for pharmaceutical and agro-
chemical applications,41–46 we decided to introduce a fluorine atom
onto the triazoloquinoline unit. The double metalation of tri-
azoloquinoline 1 afforded, after trapping of the dilithiated in-
termediate with 3 equiv of N-fluorobenzenesulfonimide (NFSI,
Accufluor), exclusively the monofluorinated product 10 in a yield of
60% (Scheme 6). The outcome of the reaction revealed re-
producible. Even when different sources of NFSI were employed, no
Figure 2. Metalation of triazoloquinoline 1 at C3 and trapping with CD3OD.

R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
4413
difluorinated product could be detected. Acid-mediated ring
H
opening of the triazoloquinoline ring afforded in excellent yield the
9-fluoroquinoline 11.
H3O
X
H
X
X
H
N
N
N
N
N
X
X
N2
X
X
N
X
N2
- N2
H2O
i) BuLi (3.0 eq.)
THF -78 °C, 2h
H2O
- X
N
N
N
N
H
X
ii) NFSI (3.0 eq.)
OH2
F
N
N
N
N
N
- H
O
OH
X
1
10 (60%)
Scheme 8.
i) HOAc
reflux, 8h
N
N
N
quinoline (7d) the ring opening only occurred when 7 M sulfuric
acid was employed affording quinoline 12c.
The presumable mechanism for the ring opening reaction is
similar to the one published before,21,49,50 and is depicted in
Scheme 8.
F
O
F
11 (70%)
10
O
Scheme 6.
The metalation/ring opening chemistry of the triazole scaffold
opens a convenient new way to 9-fluorinated triazoloquinolines
and 8-fluoroquinolines. In this way, 2-(functionalized)-8-fluoro-
quinolines become readily accessible compared to more classical
conditions.47,48
In order to study the scope and limitation of the use of 3,9-
dihalogenated triazoloquinolines in the synthesis of 2,8-di-
substituted quinolines, we studied more in detail their ring opening
reaction. So far, no examples of ring opening reactions on C3-
halogen-containing triazolopyridines or triazoloquinolines are
described in the literature. When the triazole ring of 3,9-diiodo-
[1,2,3]triazolo[1,5-a]quinoline (7b) was submitted to a ring opening
reaction in a THF/water/HOAc (8:2:2) mixture at reflux, the alde-
hyde 12a was obtained in a yield of 90% (Scheme 7). Another
3. Conclusions
We could show, that the functionalization of [1,2,3]triazolo[1,5-
a]quinoline by means of deprotonative metalation provides new
precursors of potential pharmaceutical and biological interest. The
outcome and regioselectivity of metalation reactions were studied.
For the first time, C3-halogen-containing triazoloquinoline systems
were submitted to a ring opening reaction. By this synthetic
pathway, the triazole ring (which can be easily introduced by the
hydrazine/MnO2 method starting from quinoline aldehyde) has
been used as protecting and activating group of 2-quinoline-
carboxaldehydes providing highly substituted molecules with
compatible substituent pattern toward subsequent functionaliza-
tions (Fig. 3).
HCl traces
RT, 24h
X = I
THF/H2O/HOAc
= 8:2:2, reflux
X = I
OH
H
N
N
H
H
X
N
N
N
N
O
I
O
I
O
X
X
O
N
X
N
12a (90%)
12d (89%)
N
7b-d
X
N
Figure 3. The triazole ring as
a new protecting and 9-activating group toward
8-substituted quinolines.
H2SO4 (7M)
reflux
H2SO4 (2.5M)
reflux
H
H
N
O
N
X = Cl
X = Br
Br
Cl
O
4. Experimental section
4.1. General
12b (81%)
12c (77%)
Scheme 7.
Starting materials, if commercial, were purchased and used as
such, provided that adequate checks (melting ranges, refractive
indices, and gas chromatography) had confirmed the claimed pu-
rity. When known compounds had to be prepared according to
literature procedures, pertinent references are given. Air- and
moisture-sensitive materials were stored in Schlenk tubes. They
were protected by and handled under an atmosphere of argon,
using appropriate glassware. Tetrahydrofuran was dried by distil-
lation from sodium after the characteristic blue color of sodium
diphenyl ketyl (benzophenone-sodium ‘radical-anion’) had been
found to persist. Ethereal or other organic extracts were dried by
washing with brine and then by storage over sodium sulfate.
Melting ranges (mp) given were determined on a Kofler heated
stage and found to be reproducible after recrystallization, unless
stated otherwise (‘decomp.’), and are uncorrected. If melting points
are missing, it means all attempts to crystallize the liquid at tem-
peratures down to –75 ꢁC failed. Column chromatography was
carried out on a column packed with silica gel 60 N spherical
possibility to undergo a triazole ring opening toward ketones or
aldehydes frequently employed in triazolopyridine chemistry is the
use of SeO2 as oxidant. However, 3-halogenated triazoloquinolines
undergo exclusively aldehyde formation. In this context, the high
acid-sensitivity of 3,9-diiodo-[1,2,3]triazolo[1,5-a]quinoline (7b)
has to be pointed out. We mentioned already above (Scheme 4),
that 9-iodo-3-(trimethylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (8)
could not be purified due to its decomposition on silica. Similarly,
when 3,9-diiodo-[1,2,3]triazolo[1,5-a]quinoline (7b) was kept in an
NMR tube, traces of HCl present in deuterio chloroform were suf-
ficient to induce the ring opening affording the acid 12d in an ex-
cellent yield (Scheme 8).
In contrast, the corresponding dibromo and dichloro derivates 7c
and 7d underwent the ring opening only under more drastic reaction
conditions. For 3,9-dibromo-[1,2,3]triazolo[1,5-a]quinoline (7c),
heating under reflux in 2.5 M sulfuric acid was required to obtain the
analogous quinoline 12b. In case of 3,9-dichloro-[1,2,3]triazolo[1,5-a]-
neutral size 63–210 m
m. 1H and (1H decoupled) 13C nuclear

4414
R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
magnetic resonance (NMR) spectra were recorded at 400 or 300
and 101 or 75 MHz, respectively. Chemical shifts are reported in
4.5. 3-Iodo-[1,2,3]triazolo[1,5-a]quinoline (2d)
d
units, parts per million (ppm) and were measured relative to the
Prepared analogously as compound 2a and trapping of the
lithiated intermediate with a solution of iodine (2.41 g, 9.5 mmol,
1.6 equiv) in tetrahydrofuran (15.0 mL) affording 3-iodo-[1,2,3]tri-
azolo[1,5-a]quinoline (2d) as a white solid (1.22 g, 70%). Mp 136–
signals for residual chloroform (7.27 ppm). Coupling constants J are
given in Hz. Coupling patterns are abbreviated as, for example, s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), td
(triplet of doublets), m (multiplet), app. s (apparent singlet), and br
(broad). COSY experiments were performed for all compounds.
Details regarding standard operations and abbreviations can be
found in previous publications from this laboratory.51–53
138 ꢁC; 1H NMR (300 MHz, CDCl3):
d 8.76 (1H, d, J 8.3 Hz, 9-H), 7.87
(1H, dd, J 7.9 and 1.0 Hz, 6-H), 7.74 (1H, ddd, J 8.3, 7.9, and 1.0 Hz, 8-
H), 7.67–7.57 (2H, m, 7-H, 4-H), and 7.41 (1H, d, J 9.3 Hz, 5-H); 13C
NMR (75 MHz, CDCl3):
d 134.2 (C), 131.6 (C), 130.2 (CH), 128.5 (CH),
127.6 (CH), 127.4 (CH), 123.9 (C), 115.9 (CH), 114.2 (CH), and 81.7 (C);
HRMS (ESI-TOF) calcd for C10H6IN3 [MþNa]þ: 317.9499, found:
317.9458.
4.2. 3-Methyl-[1,2,3]triazolo[1,5-a]quinoline (2a)
At 0 ꢁC, butyllithium (3.94 mL, 5.92 mmol, 1.0 equiv) in hexanes
(1.5 M) was added to a solution of 2,2,6,6-tetramethylpiperidine
(0.99 mL, 0.83 g, 5.92 mmol, 1.0 equiv) in tetrahydrofuran
(50.0 mL). After 15 min, the mixture was cooled to ꢀ78 ꢁC and
canulated into a solution of [1,2,3]triazolo[1,5-a]quinoline (1)
(0.99 g, 5.91 mmol, 1.0 equiv) in tetrahydrofuran (75.0 mL). The
mixture was kept for 2 h at ꢀ78 ꢁC before iodomethane (0.62 mL,
1.42 g, 10.0 mmol, 1.7 equiv) was added and allowed to reach 20 ꢁC
in the course of 1 h. A saturated aqueous solution of ammonium
chloride (20.0 mL) was added and the product extracted into
dichloromethane (3ꢂ50.0 mL), washed with brine (10.0 mL), and
dried over Na2SO4. The product was purified by flash chromatog-
raphy on silica gel using a gradient of ethyl acetate/cyclohexane to
give 3-methyl-[1,2,3]triazolo[1,5-a]quinoline (2a) as a yellow solid
4.6. 3-(p-Tolylsulfinyl)-[1,2,3]triazolo[1,5-a]quinoline (2e)
Prepared analogously as compound 2a and trapping of the
lithiated intermediate by addition into a solution of (1R,2S,5R)-
(ꢀ)-menthyl-(S)-p-toluenesulfinate (2.21 g, 7.40 mmol, 1.3 equiv)
in tetrahydrofuran (50.0 mL) at ꢀ45 ꢁC. Usual workup and purifi-
cation by flash chromatography on silica gel using a gradient of
ethyl acetate/cyclohexane (from 1:3 to 1:1) afforded 3-(p-tolyl-
sulfinyl)-[1,2,3]triazolo[1,5-a]quinoline (2e) as a white solid (1.49 g,
22
82%). Mp 145–147 ꢁC; [
a
]
D
þ104.2 (c 1, acetone); 1H NMR
(300 MHz, CDCl3): d 8.78 (1H, d, J 8.4 Hz, 9-H), 7.87 (1H, dd, J 7.9 and
1.0 Hz, 6-H), 7.81 (1H, ddd, J 8.4, 7.3, and 1.2 Hz, 8-H), 7.71 (3H, m,
20-H(p-Tol), 4-H), 7.63 (2H, m, 7-H, 5-H), 7.32 (2H, d, J 8.0 Hz, 30-
H(p-Tol)), and 2.39 (3H, s, CH3 (p-Tol)); 13C NMR (75 MHz, CDCl3):
(0.93 g, 86%). Mp 114–115 ꢁC; 1H NMR (300 MHz, CDCl3):
d
8.74 (1H,
d 142.4 (C), 141.7 (C), 140.3 (C), 131.7 (C), 131.1 (C), 130.7 (CH), 130.1
d, J 8.0 Hz, 9-H), 7.80 (1H, dd, J 7.9 and 0.9 Hz, 6-H), 7.72 (1H, ddd, J
8.0, 7.8, and 0.9 Hz, 8-H), 7.56 (1H, dd, J 7.9 and 7.8 Hz, 7-H), 7.42
(2H, app. s, 5-H, 4-H), and 2.64 (3H, s, CH3); 13C NMR (75 MHz,
(2ꢂCH), 129.1 (CH), 128.7 (CH), 127.9 (CH), 124.6 (2ꢂCH), 124.0 (C),
116.4 (CH), 114.4 (CH), and 21.4 (CH3); HRMS (EI) calcd for
C17H13N3OS: 307.0779, found: 307.0784.
CDCl3):
d 136 (C), 132 (C), 129.8 (CH), 129.3 (C), 127.7 (CH), 126.5
(CH), 124.8 (CH), 123.8 (C), 115.7 (CH), 114.1 (CH), and 10.0 (CH3);
HRMS (EI) calcd for C11H9N3: 183.0796, found: 183.0800. Anal.
Calcd for C11H9N3 (183.21): C, 71.11; H, 4.95; N, 22.94. Found: C,
71.54; H, 5.04; N, 23.04.
4.7. 9-Methyl-[1,2,3]triazolo[1,5-a]quinoline (6)
At 25 ꢁC, tetrabutylammonium fluoride (1.20 mL, 1.20 mmol,
1.9 equiv) in tetrahydrofuran (1 M) was added to a solution of 9-
methyl-3-(trimethylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (9) (0.15 g,
0.60 mmol,1.0 equiv) in tetrahydrofuran (15.0 mL). After 1 h at 25 ꢁC,
asaturatedaqueous solutionofsodiumchloride(20.0 mL)wasadded.
The product was extracted into dichloromethane (3ꢂ50 mL), washed
withbrine(10.0 mL)anddriedoverNa2SO4. Flashchromatographyon
silica gel using a mixture of ethyl acetate/cyclohexane (2:3) gave 9-
methyl-[1,2,3]triazolo-[1,5-a]quinoline (6) as a colorless solid (0.10 g,
4.3. 3-(Deuterio)-[1,2,3]triazolo[1,5-a]quinoline (2b)
Prepared analogously as compound 2a starting from [1,2,3]tri-
azolo[1,5-a]quinoline (1) (0.49 g, 2.9 mmol, 1 equiv) and trapping
of the lithiated intermediate with excess methanol-d4 (1.00)
affording 3-(deuterio)-[1,2,3]triazolo[1,5-a]quinoline (2b) as an
orange solid (0.48 g, 96%). Mp 81–83 ꢁC; 1H NMR (300 MHz, CDCl3):
92%). Mp 102–103 ꢁC; 1H NMR (300 MHz, CDCl3):
7.60(1H, d, J7.7 Hz, 6-H), 7.50 (1H, d,J 7.2 Hz, 8-H), 7.5–7.4(3H, m, 7-H,
5-H, 4-H), and 3.16 (3H, s, 9-CH3); 13C NMR (75 MHz, CDCl3):
132.9
d 8.04 (1H, s, 3-H),
d
8.71 (1H, d, J 8.3 Hz, 9-H), 7.76 (1H, dd, J 7.9 and 1.0 Hz, 6-H), 7.69
(1H, dd, J 8.3 and 7.7 Hz, 8-H), 7.5–7.4 (2H, m, 4-H, 7-H), and 7.44
(1H, d, J 9.3 Hz, 5-H); 13C NMR (75 MHz, CDCl3):
131.8 (C), 131.6
d
(CH), 132.7 (C), 131.6 (C), 129.5 (C), 127.6 (CH), 126.3 (CH), 126.2 (CH),
126.0 (CH), 125.2 (C), 114.2 (CH), and 24.3 (CH3); HRMS (EI) calcd for
C11H9N3: 183.0796, found: 183.0791.
d
(C), 130.0 (CH), 128.5 (CH), 127.3 (C, t, JC–D 29.9 Hz, CD), 127.0 (CH),
126.6 (CH), 123.8 (C), 116.2 (CH), and 114.7 (CH).
4.8. 3,9-Dimethyl-[1,2,3]triazolo[1,5-a]quinoline (7a)
4.4. 3-(Trimethylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (2c)
At ꢀ78 ꢁC, butyllithium (2.36 mL, 3.54 mmol, 3.0 equiv) in
hexanes (1.5 M) was added to a solution of [1,2,3]triazolo[1,5-
a]quinoline (1) (0.19 g, 1.18 mmol, 1.0 equiv) in tetrahydrofuran
(15.0 mL). After 2 h at ꢀ78 ꢁC, iodomethane (0.24 mL, 0.54 g,
3.8 mmol, 3.2 equiv) was added and allowed to reach 20 ꢁC in the
course of 1 h. A saturated aqueous solution of ammonium chloride
(20.0 mL) was added and the product extracted into dichloro-
methane (3ꢂ50.0 mL), washed with brine (10.0 mL), and dried over
Na2SO4. The product was purified by flash chromatography on silica
gel using a 1:1 mixture of ethyl acetate/cyclohexane as eluent,
which provided 3,9-dimethyl-[1,2,3]triazolo[1,5-a]quinoline 7a as
a yellow solid (0.19 g, 82%). Mp 84–85 ꢁC; 1H NMR (300 MHz,
Prepared analogously as compound 2a and trapping of the
lithiated intermediate with chlorotrimethylsilane (1.26 mL, 1.09 g,
10 mmol, 1.7 equiv) affording 3-(trimethylsilyl)-[1,2,3]triazolo[1,5-
a]quinoline (2c) as an orange solid (1.37 g, 96%). Mp 99–101 ꢁC; 1H
NMR (300 MHz, CDCl3):
d 8.80 (1H, d, J 8.3 Hz, 9-H), 7.76 (1H, dd, J
7.9 and 1.1 Hz, 6-H), 7.69 (1H, ddd, J 8.3, 7.9 and 1.1 Hz, 8-H), 7.6–7.5
(2H, m, 7-H, 4-H), 7.46 (1H, d, J 9.3 Hz, 5-H), and 0.49 (9H, s,
Si(CH3)3); 13C NMR (75 MHz, CDCl3):
d 139.4 (C), 136.8 (C), 132.2 (C),
129.8 (CH), 128.3 (CH), 126.8 (CH), 126.3 (CH), 123.7 (C), 116.7 (CH),
115.0 (CH), and ꢀ0.76 (3ꢂCH3); HRMS (EI) calcd for C13H15N3Si:
241.1035, found: 241.1032.
CDCl3):
d 7.62 (1H, dd, J 7.7 and 0.9 Hz, 6-H), 7.51 (1H, dd, J 7.4 and

R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
4415
0.9 Hz, 8-H), 7.43 (1H, dd, J 7.7 and 7.4 Hz, 7-H), 7.38 (2H, app. s, 4-H,
[1,2,3]triazolo[1,5-a]quinoline (2c) (0.19 g, 0.80 mmol, 1.0 equiv) in
tetrahydrofuran (15.0 mL). After 2 h at ꢀ78 ꢁC, iodine (0.24 g,
0.96 mmol, 1.2 equiv) in THF (5.0 mL) was added and the mixture
allowed to reach 20 ꢁC. The product was characterized by HRMS as
the product degrades during purification. HRMS (EI) calcd for
C13H14IN3Si: 367.0001, found: 366.9999.
5-H), 3.18 (3H, s, 9-CH3), and 2.63 (3H, s, 3-CH3); 13C NMR (75 MHz,
CDCl3):
d 134.7 (C), 132.8 (CH), 131.9 (C), 130.4 (C), 129.6 (C), 126.4
(CH), 126.3 (CH), 126.2 (CH), 125.5 (C), 114.1 (CH), 24.4 (9-CH3), and
10.2 (3-CH3); HRMS (EI) calcd for C12H11N3: 197.0952, found:
197.0949. Anal. Calcd for C12H11N3 (197.24): C, 73.07; H, 5.62; N,
21.30. Found: C, 72.65; H, 5.71; N, 21.48.
4.13. 9-Methyl-3-(trimethylsilyl)-[1,2,3]triazolo-
[1,5-a]quinoline (9)
4.9. 3,9-Diiodo-[1,2,3]triazolo[1,5-a]quinoline (7b)
Prepared analogously as compound 7a starting from [1,2,3]tri-
azolo[1,5-a]quinoline (1) (0.99 g, 5.9 mmol, 1.0 equiv) and trapping
of the lithiated intermediate with a solution of iodine (6.09 g,
24 mmol, 4.0 equiv). Crystallization from dichloromethane gave
3,9-diiodo-[1,2,3]triazolo[1,5-a]quinoline (7b) as pale yellow nee-
dles (2.06 g, 82%). Decomp. 144 ꢁC; 1H NMR (300 MHz, CDCl3):
Prepared analogously as compound 8 starting from 3-(trime-
thylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (2c) (0.19 g, 0.8 mmol,
1.0 equiv) followed by addition of iodomethane (0.11 mL, 1.76 g,
1.7 mmol, 1.2 equiv). A saturated aqueous solution of ammonium
chloride (20.0 mL) was added followed by extraction into
dichloromethane (3ꢂ50.0 mL). The combined organic extracts
were washed with brine (10.0 mL) and dried over Na2SO4 affording
3-(trimethylsilyl)-[1,2,3]triazolo[1,5-a]quinoline (9) as yellow solid
d
8.44 (1H, dd, J 7.7 and 1.3 Hz, 6-H), 7.83 (1H, dd, J 7.8 and 1.3 Hz, 8-
H), 7.52 (1H, d, J 9.3 Hz, 4-H), 7.46 (1H, d, J 9.3 Hz, 5-H), and 7.25
(1H, dd, J 7.7 and 7.8 Hz, 7-H); 13C NMR (75 MHz, CDCl3):
145.0
0.20 g (99%). Mp 106–108 ꢁC; 1H NMR (300 MHz, CDCl3):
d, J 8.1 Hz, 6-H), 7.6–7.5 (2H, m), 7.5–7.4 (2H, m), 3.21 (3H, s, CH3),
and 0.49 (9H, s, Si(CH3)3); 13C NMR (75 MHz, CDCl3):
137.9 (C),
d
7.66 (1H,
d
(CH), 134.8 (C), 133.4 (C), 129.2 (CH), 128.3 (CH), 127.9 (CH), 126.7
(2ꢂC), 115.2 (CH), and 83.2 (C); HRMS (EI) calcd for C10H5I2N3:
420.8573, found: 420.8567. Anal. Calcd for C10H5I2N3 (426.02): C,
28.53; H, 1.23; N, 9.98. Found: C, 28.00; H, 1.26; N, 9.98.
d
137.7 (C), 132.9 (CH), 132.1 (C), 129.8 (C), 127.6 (CH), 126.3 (CH),
126.2 (CH), 125 .3 (C), 115.5 (CH), 24.6 (CH3), and ꢀ0.81 (3ꢂCH3);
HRMS (EI) calcd for C14H17N3Si: 255.1191, found: 255.1201.
4.10. 3,9-Dibromo-[1,2,3]triazolo[1,5-a]quinoline (7c)
4.14. 9-Fluoro-[1,2,3]triazolo[1,5-a]quinoline (10)
Prepared analogously as compound 7a starting from [1,2,3]tri-
azolo[1,5-a]quinoline (1) (0.44 g, 2.6 mmol, 1.0 equiv) followed by
At ꢀ78 ꢁC, butyllithium (2.33 mL, 3.50 mmol, 3.0 equiv) in
hexanes (1.5 M) was added to a solution of [1,2,3]triazolo[1,5-
a]quinoline (1) (0.20 g, 1.20 mmol, 1.0 equiv) in tetrahydrofuran
addition
of
1,2-dibromo-1,1,2,2-tetrafluoroethane
(2.70 g,
10.4 mmol, 4.0 equiv) affording after crystallization from
dichloromethane/hexanes 3,9-dibromo-[1,2,3]triazolo[1,5-a]quin-
oline (7c) as pale brown needles (0.62 g, 74%). Mp 166–168 ꢁC; 1H
(15.0 mL). After 2 h at ꢀ78 ꢁC,
a
solution of N-fluoro-
dibenzenesulfonimide (1.01 g, 3.50 mmol, 3.0 equiv) in tetrahy-
drofuran (20.0 mL) was added and allowed to reach 20 ꢁC during
1 h. After addition of a saturated aqueous solution of ammonium
chloride (50.0 mL), the product was extracted into ethyl acetate
(3ꢂ50.0 mL), washed with brine (10.0 mL), and dried over Na2SO4.
Flash chromatography over silica gel using a 1:1 mixture of ethyl
acetate/cyclohexane afforded 9-fluoro-[1,2,3]triazolo[1,5-a]quino-
line (10) as a brown solid (0.14 g, 60%). Mp 109–111 ꢁC; 1H NMR
NMR (300 MHz, CDCl3):
d 8.05 (1H, dd, J 7.8 and 1.3 Hz, 6-H), 7.79
(1H, dd, J 7.9 and 1.3 Hz, 8-H), 7.53 (1H, d, J 9.3 Hz, 4-H), 7.47 (1H, d, J
9.3 Hz, 5-H), and 7.42 (1H, dd, J 7.9 and 7.8 Hz, 7-H); 13C NMR
(75 MHz, CDCl3): d 137.3 (CH), 131.4 (C), 130.8 (C), 128.4 (CH), 128.0
(CH), 127.7 (CH), 127.2 (C), 114.5 (CH), 114.4 (C), and 110.3 (C); HRMS
(ESI-TOF) calcd for C10H759Br2N3 [MþNa]þ: 347.8742, found:
347.8719; calcd for C10H759Br81BrN3 [MþNa]þ: 349.8722, found:
349.8296; calcd for C10H851Br2N3 [MþNa]þ: 351.8703, found:
351.8684. Anal. Calcd for C10H5Br2N3 (326.97): C, 36.73; H, 1.54; N,
12.85. Found: C, 36.24; H, 1.67; N, 12.64.
(300 MHz, CDCl3):
d
8.12 (1H, d, JF–H 0.4 Hz, 3-H) and 7.6–7.4 (5H,
152.8 (d, JF–C 259.5 Hz, 9-C), 132.4
m); 13C NMR (75 MHz, CDCl3):
d
(s, 2ꢂC),127.1 (d, JF–C 7.6 Hz, CH),126.8 (d, JF–C 1.5 Hz, C),126.6 (d, JF–
C 1.3 Hz, CH),126.5 (d, JF–C 2.2 Hz, CH),124.0 (d, JF–C 4.2 Hz, CH),117.1
(d, JF–C 19.5 Hz, CH), and 115.8 (d, JF–C 1.5 Hz, CH); HRMS (ESI-TOF)
calcd for C10H6FN3 [MþNa]þ: 210.0438, found: 210.0440.
4.11. 3,9-Dichloro-[1,2,3]triazolo[1,5-a]quinoline (7d)
Prepared analogously as compound 7a starting from [1,2,3]tri-
azolo[1,5-a]quinoline (1) (0.43 g, 2.6 mmol, 1.0 equiv) and trapping
of the lithiated intermediate with 1,1,2-trichloro-1,2,2-trifluoro-
ethane (1.24 mL, 1.94 g, 10.4 mmol, 4.0 equiv). After crystallization
from cold dichloromethane/hexane 3,9-chloro-[1,2,3]triazolo[1,5-
a]quinoline (7d) was obtained as pale brown needles (0.43 g, 71%).
4.15. (8-Fluoroquinolin-2-yl)methyl acetate (11)
A solution of 9-fluoro-[1,2,3]triazolo[1,5-a]quinoline (18.7 mg,
0.100 mmol, 1 equiv) in acetic acid (15.0 mL) was heated under
reflux during 8 h. After cooling to room temperature, excess acetic
acid was distilled off and the residue neutralized with a saturated
aqueous solution of sodium hydrogen carbonate (5.00 mL). The
aqueous phase was extracted with dichloromethane (3ꢂ10.0 mL),
washed with brine (10.0 mL), and dried over Na2SO4. The product
was purified by flash chromatography on silica gel using a 1:1
mixture of ethyl acetate/cyclohexane as eluent, which provided (8-
fluoroquinolin-2-yl)methyl acetate 11 as a colorless oil (15.3 mg,
Mp 169–171 ꢁC; 1H NMR (300 MHz, CDCl3):
1.1 Hz, 6-H), 7.71 (1H, dd, J 7.9 and 1.1 Hz, 8-H), and 7.5–7.4 (3H, m, 7-
H, 4-H, 5-H); 13C NMR (75 MHz, CDCl3):
133.3 (CH),129.4 (C),129.1
(C), 127.8 (C), 127.7 (CH), 127.6 (CH), 127.3 (CH), 126.9 (C), 123.9 (C),
and 113.9 (CH); HRMS (ESI-TOF) calcd for C10H355Cl2N3 [MþNa]þ:
259.9753, found: 259.9774; calcd for C10H355Cl37ClN3 [MþNa]þ:
261.9724, found: 261.9748; calcd for C10H357Cl2N3 [MþNa]þ:
263.9697, found: 263.9736. Anal. calcd for C10H5Cl2N3 (238.07): C,
50.45; H, 2.12; N, 17.63. Found: C, 50.20; H, 2.37; N, 17.22.
d 7.76 (1H, d, J 7.9 and
d
70%). 1H NMR (300 MHz, CDCl3):
d 8.14 (1H, dd, J 8.6 and 1.5 Hz, 4-
H), 7.54 (1H, d, J 8.0 Hz, 5-H), 7.41 (1H, d, J 8.6 Hz, 3-H), 7.4–7.3 (2H,
4.12. 9-Iodo-3-(trimethylsilyl)-[1,2,3]triazolo[1,5-a]-
m, 6-H, 7-H), 5.38 (2H, s, CH2), and 2.13 (3H, d, J 3.5 Hz, CH3); 13C
quinoline (8)
NMR (75 MHz, CDCl3): d 170.6 (COO), 157.9 (d, JF–C 256.9 Hz, 8-C),
156.7 (d, JF–C 1.5 Hz, C), 137.9 (d, JF–C 11.7 Hz, C), 136.7 (d, JF–C 3.1 Hz,
CH), 129.4 (d, JF–C 2.2 Hz, C), 126.5 (d, JF–C 8.0 Hz, CH), 123.3 (d, JF–C
4.7 Hz, CH), 120.3 (CH), 113.9 (d, JF–C 19.0 Hz, CH), 67.3 (CH2), and
At ꢀ78 ꢁC, butyllithium (0.90 mL, 1.40 mmol, 1.7 equiv) in hex-
anes (1.5 M) was added to
a solution of 3-(trimethylsilyl)-

4416
R. Ballesteros-Garrido et al. / Tetrahedron 65 (2009) 4410–4417
20.9 (CH3); HRMS (ESI-TOF) calcd for C12H10FNO2 [MþNa]þ:
(C), 144.3 (C), 137.9 (CH), 134.9 (C), 131.4 (C), 130.6 (CH), 129.1 (CH),
35
242.0588, found: 242.0554.
126.9 (CH), and 118.1 (CH); HRMS (ESI-TOF) calcd for C H ClNO
10 6
[MþLi]þ: 198.0293, found: 198.0297; calcd for C10H367ClNO
4.16. 8-Iodoquinoline-2-carbaldehyde (12a)
[MþLi]þ: 200.0276, found: 200.0265.
3,9-Diiodo-[1,2,3]triazolo[1,5-a]quinoline (7b) (0.13 g, 0.30 mmol,
1.0 equiv) was diluted in a mixture of water (8.00 mL), tetrahydro-
furan (2.00 mL), and acetic acid (2.00 mL), and heated to reflux. The
reaction, becoming deep red when the reagent was completely
consumed, was monitored by TLC. Upon completion of the reaction
(4 h), acetic acid was separated by distillation and the reaction mix-
ture was quenched with a saturated aqueous solution of sodium
thiosulphate (20.0 mL), observing the disappearance of the red col-
oration. The mixture was treated with a saturated aqueous solution of
sodium hydrogen carbonate (5.0 mL) until pH 8 and the product
extracted into dichloromethane (3ꢂ50.0 mL). The organic layers
were combined, washed with brine (20.0 mL), and dried over Na2SO4.
Flash column chromatography on silica gel using a gradient ethyl
acetate/cyclohexane (1:5 to 2:1) gave 8-iodoquinoline-2-carbalde-
hyde (12a) as a yellow solid (76.4 mg, 90%). Mp 149–151 ꢁC; 1H NMR
4.19. 8-Iodoquinoline-2-carboxylic acid (12d)
In a NMR tube 3,9-diiodo-[1,2,3]triazolo[1,5-a]quinoline (7c)
(13 mg, 0.03 mmol, 1.0 equiv) was dissolved in [2H]chloroform
(0.7 mL) affording a pink coloration becoming deep purple after
24 h. 1H NMR (300 MHz, CDCl3):
d 11.34 (1H, br s, COOH), 8.46 (1H,
dd, J 7.4 and 1.20 Hz, 5-H), 8.40 (1H, d, J 8.4 Hz, 3-H), 8.32 (1H, d, J
8.4 Hz, 4-H), 7.95 (1H, dd, J 8.2 and 1.2 Hz, 7-H), and 7.45 (1H, dd, J
8.2, 7.4 Hz, 6-H); 13C NMR (75 MHz, CDCl3):
d 163.4 (C), 146.6 (C),
144.8 (C), 142.5 (CH), 139.9 (CH), 130.3 (CH,C), 128.6 (CH), 120.1
(CH), and 103.0 (C); HRMS (ESI-TOF) calcd for C10H6INO2 [MþNa]þ:
321.9335, found: 321.9312.
Acknowledgements
(300 MHz, CDCl3): d 10.30 (1H, s, CHO), 8.44 (1H, dd, J 7.4 and 1.2 Hz,
`
This work was financially supported by the the Ministere de la
5-H), 8.25 (1H, d, J 8.4 Hz, 3-H), 8.05 (1H, d, J 8.4 Hz, 4-H), 7.89 (1H, dd,
´
Recherche (France), the Ministerio de Educacion y Ciencia (Spain)
(Project CTQ2006-15672-C05-03), the CNRS (France). R.B.-G. is
much indebted to the Ministere de l’Education Nationale, de la
Recherche et de la Technologie (France) for a doctoral fellowship.
J 8.2 and 1.2 Hz, 7-H), and 7.39 (1H, dd, J 8.2 and 7.4 Hz, 6-H); 13C NMR
(75 MHz, CDCl3):
d 193.4 (CH), 153.4 (C), 146.8 (C), 141.2 (CH), 138.3
´
`
(CH),130.7 (C),130.1 (CH),128.7 (CH),118.1 (CH), and 104.8 (C); HRMS
(ESI-TOF) calcd for C10H6INO [MþLi]þ: 289.9649, found: 289.9640.
Anal. Calcd for C10H6INO (283.07): C, 42.30; H, 2.14; N, 4.830. Found:
C, 42.30; H, 2.43; N, 4.83.
References and notes
1. Morimoto, Y.; Matsuda, F.; Shirahama, H. Synlett 1991, 201–203.
2. Isobe, M.; Nishikawa, T.; Yamamoto, N.; Tsukiyama, T.; Ino, A.; Okita, T. J. Het-
erocycl. Chem. 1992, 29, 619–625.
4.17. 8-Bromoquinoline-2-carbaldehyde (12b)
3. Michael, J. P. Nat. Prod. Rep. 1997, 14, 605–618.
3,9-Dibromo-[1,2,3]triazolo[1,5-a]quinoline
(7c)
(98.1 mg,
4. Markees, D. G.; Dewey, V. C.; Kidder, G. W. J. Med. Chem. 1970, 13, 324–326.
5. Campbell, S. F.; Hardstone, J. D.; Palmer, M. J. J. Med. Chem. 1988, 31, 1031–1035.
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0.30 mmol, 1.0 equiv) was diluted in aqueous sulfuric acid (10.0 mL,
2.5 M) and heated to reflux. The reaction was monitored by TLC.
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of sodium hydrogen carbonate (5.0 mL) was added until pH 8. The
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acetate/cyclohexane (1:5 to 2:1) gave 8-bromoquinoline-2-carbal-
dehyde (12b) as a yellow solid (57.4 mg, 81%). Mp 135–137 ꢁC; 1H
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8.3 Hz, 7-H), and 7.53 (1H, dd, J 8.3 and 7.5 Hz, 6-H); 13C NMR
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(CH), 131.3 (C), 129.4 (CH), 127.7 (CH), 126.1 (C), and 118.0 (CH);
HRMS (ESI-TOF) calcd for C10H769BrNO [MþLi]þ: 241.9788, found:
241.9756; calcd for C10H681BrNO [MþLi]þ: 243.9768, found:
243.9736.
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3,9-Dichloro-[1,2,3]triazolo[1,5-a]quinoline
(7d)
(0.14 g,
0.6 mmol, 1.0 equiv) was diluted in aqueous sulfuric acid (15.0 mL,
7 M) and heated to reflux. The reaction was monitored by TLC. Upon
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129–131 ꢁC; 1H NMR (300 MHz, CDCl3):
d 10.32 (1H, s, CHO), 8.35
(1H, d, J 8.4 Hz, 3-H), 8.11 (1H, d, J 8.4 Hz, 4-H), 7.95 (1H, dd, J 7.5 and
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8.2 and 7.5 Hz, 6-H); 13C NMR (75 MHz, CDCl3):
d 193.4 (CHO), 152.9

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